Imagine you could restore health and lose weight by eating fats and protein and consuming fewer carbohydrates, i.e. sugar and grains. This was standard medical advice up until the late 1970s. Then the advice changed to “eat more grains and limit saturated fats”. The new “healthy eating” advice was never subjected to rigorous testing before the old advice, which had served society well, was ignominiously dumped. Are we, as a nation, now fitter, better nourished, and less disease prone as a result?

The Kiwi ANZACs, widely considered to be the fittest troops in the Allied armies in two world wars, were raised in a nation where per capita weekly butter consumption was 415 grams. It is now 112 grams, which is half of the reduced 1940s wartime ration. The consumption of fat from red meat has also decreased as drastically. We eat fewer eggs and drink less full-fat milk.

There is a fallacy that stems initially from the Western intellectual's sense of cultural inadequacy and guilt, and the assumption that Eastern cultures must somehow be purer and wiser. One of the features of Eastern religious culture identified early on by aficionados like Schopenhauer – because the things that are unusual in a culture attract attention first - was vegetarianism. The reality of Buddhist and Hindu society, like all successful human society, didn't involve denial of animal foods (the Dalai Lama eats meat, observant Hindus cook with butter fat), but the ideal, already present in Western ascetic tradition and not associated there with robust physical or mental health, had a persistent appeal, which found expression in the early temperance, vegetarian and vegan movements.

We then come to a point in history - the 60's - 70's counterculture - where the idea took hold more widely, through music and other popular media, that vegetarianism (and other aspects of Eastern religious thought) represented the higher path, while the habits of the older generation were anathematized; including church-going, smoking, drinking, meat eating.

Various influential people exposed to this assumption in their formative years unconsciously accepted it as factual. The same bias can be seen to persist today when veganism, despite its risks, is accepted as normal by government dieticians as somehow being worth nurturing as the expression of a noble and virtuous impulse; whereas the Atkins type of high fat, low carb diet is not to be encouraged, despite the scientific evidence in its favour and common-sense assessments of its nutritive value, because it is seen as self-indulgent. Deep psychological forces decide the values different foods are given, and mystical, revolutionary, and puritanical impulses as well as economic and social pressures distort the collection, interpretation and publication of data.

Scientific research has been misinterpreted to reflect an existing prejudice, and this has suited the food manufacturing industry, with novel oil, grain, and soy products to find markets for. A perfect storm of error has formed around the question of fat, because of the earlier invention of the cholesterol test, which seemed to support the new belief, and which lent it a spurious validity. The animal fat in our diets has been the ultimate casualty.

Most people cannot stay vegetarian for good reasons, and many backslide, but not all the way, only to the "vegan meat" chicken, to lean meats, low fat dairy and so on. It's as if by avoiding what one thinks is "saturated" fat one can avoid the sinful aspects of consuming flesh. The very word “saturated”, a technical description of chemical bonds, conveys unintended connotations of excess.

Yet highly saturated fats like beef dripping and coconut oil have a remarkable ability to protect the liver from the toxicity of alcohol or other drugs. Polyunsaturated fats have the opposite effect. That seems like something that should be more widely known, instead of confined to those medical journals that specialize in alcoholism. It should also be more widely known that people who eat the most dairy fat have half the diabetes incidence of the people who eat the least, or that, all over the world, those who attempt suicide tend to have significantly lower cholesterol levels than those who do not. And so on.

It was studying the life cycle of the hepatitis C virus (HCV) that eventually forced me to question my received beliefs about fat, carbohydrate, and cholesterol:

- HCV depresses and monopolises cholesterol production; cholesterol in the diet counteracts this.
- HCV uses VLDL to exit infected cells; starches and sugars increase VLDL production.

- Saturated fats in a low-carbohydrate diet (and omega 3 oils from fatty fish) decrease it.
- HCV infects new cells through the LDL receptor; polyunsaturated vegetable oils increase the number of LDL receptors.

- If you have Hepatitis C, your prospects improve with higher LDL levels (a sign of fewer LDL receptors).
- HCV depresses immunity by sequestering zinc and selenium; these minerals are most easily absorbed from fatty foods like meat, seafood and Brazil nuts; their absorption is inhibited by most grains and legumes.

- The antioxidants from leafy vegetables, fruits and berries are valuable, but they are no substitute for animal fats and carbohydrate restriction when it comes to clearing a fatty liver, reducing viral replication, or preventing disease progression.

In the case of at least two diseases, the not uncommon ones of hepatitis C and alcoholism, the two main causes of cirrhosis and primary liver cancer in this country, current “healthy eating” advice can only be increasing harms. Fast food is not so different; fries are vegetable starch cooked in polyunsaturated vegetable seed oil, supposed to be a healthy alternative to animal fat because it “lowers cholesterol”.

Nutritional epidemiologists write papers about the French paradox, whereby the French, who have largely preserved their traditional diets, diets which happen to be rich in animal fats, have relatively low levels of heart disease, and also low rates of liver cirrhosis relative to the amount of alcohol consumed in France. In the case of the Israeli paradox, this health-conscious population has adopted modern ideas about healthy eating, especially that of reducing saturated fat by substituting polyunsaturated vegetable oils for animal fats, and now has relatively high rates of cardiovascular disease, diabetes, obesity and cancer. That these results are considered paradoxical because they contradict unproven assertions should be an embarrassment to science.

(paradox, n. Statement contrary to received opinion; statement that, whether true or not, seems absurd at first hearing; person or thing conflicting with preconceived notions of the reasonable or possible.)

Knowing all this, and also considering what our hardier ancestors might once have eaten, and what they could not have eaten, takes us back to the days before the cholesterol craze, before the food processing industry cashed in on vegetarian values, before dieticians became anserine media hacks. Sugars, grains and legumes, and seed oils, as well as the vast array of novel foods made with them, are worth limiting or avoiding. To avoid obesity, to treat diabetes and degenerative diseases, restrict carbohydrates. Fat is your friend, cholesterol is an essential part of your body, and animal foods are the most nutritious foods, with vegetable foods as valuable supplements.

Inquiry into diet has always been part of the philosophical tradition, for example in the writings of Lucretius, Montaigne, Lichtenberg, Schopenhauer and Nietzsche, because nutrition science is, or should be, concerned with the same questions as philosophy; how do we know what we know?, and, how should we live our lives? The well-designed experiment that can settle a question will always be a commodity that is valuable precisely because it is rare. Since the existence of the deficiency diseases and the harmful effects of smoking and excessive alcohol consumption were proven many years ago it has become unusual for diet and lifestyle studies to generate results that justify sweeping statements or universal recommendations. Nothing in biology makes sense except in the light of evolution, and it is only in the light of human evolution that we can hope to make sense of the human diet and its link to disease.

Originally published in the Café Reader, a fine literary magazine produced by the New Zealand-based company Phantom Billstickers.

"I forget most of what I have read, just as I do most of what I have eaten, but I know that both contribute no less to the conservation of my mind and my body on that account." - Georg Christop Lichtenberg on food frequency questionnaires.

I've procrastinated about this ever since Peter Hyperlipid posted his own classic eating update a while back, trying to contextualize what purpose a similar post of my own might serve. Ah-Ha! I see. OK then.
Basically, it's good to know these things can be done, are being done, and the reasons for certain decisions are probably worth revisiting.

Music by Mink - a lost treasure from 1996, "Your Bad Example".

Wake up - too early, give a brother some rest, my start is 6am these days which means coffee. Strong with cream and maybe if it's too strong a little soft brown sugar but, like, 1-2g, which is plenty sweet if you eat low carb, yet not enough to contribute to the world's fructose problem. Might have 2 or 3 coffees like this in the day (almost all without sugar). If it's instant coffee I'll stick a teabag in it because - I should have taken out a patent - this makes instant coffee taste like fresh coffee. Yup, I'm a wild and crazy guy, livin' on the edge now.

Coffee, as any fule kno, has powers to protect the liver in every study you can think of, and enhances the response to combination therapy in Hep C. Nice work if you can get it, as a poor liver function can slow caffeine metabolism and make you intolerant of coffee. So a little chicken-and-egg but still, there are solid biochemical reasons why both caffeine and coffee polyphenols of the caffeic acid family ought to inhibit fibrosis etc. (for example, caffeine blocks adenosine receptors, adenosine released from damaged cells serves as a chemoattractant "stop" signal for hepatic stellate cells, these cells remodel collagen matrix, caffeine is switching off their GPS. Caffeic acid phenethyl ester, CAPE, which you will also find in propolis and which is a normal metabolite of other dietary polyphenols, inhibits HCV replication. And so on.)

Other drinks I might enjoy, because I don't drink coffee after the early afternoon, include well water, green tea, black tea, red bush tea (aspalanthus, rooibos) or hibiscus flower.

Breakfast I will try to have at 10am. I used to be stricter about food-window IF but now that my appetite is tamed I'm more concerned with getting sufficient energy so will eat outside of opening hours if I feel hungry. And if I'm going out for the day I have to eat early anyway. Breakfast is fairly consistent:
3 rashers bacon (chopped small), or occasionally most of a tin of sardines (the dog gets one) or a few kidneys or a chicken liver or two. Fried slowly in a tablespoon of beef and lamb dripping (AKA tallow). This takes care of excess PUFA in the bacon, as I add one large tomato, chopped (for the potassium and carotenoids), a tablespoon of butter (or two or more if I need extra energy), a teaspoon of crushed garlic, 2 (or 3) egg yolks, a bit of any gelatine broth I have lying around, spice and salt if needed. (Note; I use various pre-mixed Indian spice mixes, masalas. I only buy masalas that contain salt - chat - as an ingredient, as this shows attention has been paid to creating a rounded flavour). So any linoleic acid in the bacon or yolks has been diluted by the more saturated fats of the dripping and butter and shouldn't matter in the greater scheme of things.

Snacks - might or might not want these in the afternoon, which might be 25g dark chocolate, or a handful of almonds, 4 Brazil nuts for the selenium, or some cold meat left over from the night before. Probably a little fruit too; at the moment, that's mandarins, kiwifruit, persimmons. Used to eat cheese but I'm a bit allergic so trying to quit. If it's a higher-carb day - or I feel like it - I'll have a banana.

Dinner (served around 6pm): some meat (could be lamb shoulder chop, if it's chicken I'll stuff it with bacon, rolled oats, butter, sage, onions and fish sauce to up the SFA content). Or could be chicken or fish cooked in coconut cream. Or beef shin bone slowly cooked in a stew with one potato, carrots, onions.
But assuming it's the lamb chops, then a lower-carb vege good for fat-soaking will be roasted with them. Pumpkin, sweet potato, oca yam, whole garlic. Roasted Brussels sprouts are pretty special IMO. Any greens - leek, Chinese cabbage, spinach - will be comfited in butter (fried slowly with lots of butter till it goes soft). Boiled carrots, steamed green beans, mashed parsnip with cream, roasted beetroot are optional but welcome. I probably eat about 200g meat, which supplies about 40-50g protein. I prefer ruminant fat, so if the meat is chicken or pork I'll find a way to include more butter or dripping in the veges. I'm not against olive oil but find I have fewer occasions to eat it.

I'll have a cup of black tea after dinner because of some superstition about iron absorption, though I tend to agree with G. C. Lichtenberg, the best thing you can add to a meal is to remove drinking from the experience.

Dessert might be 2 teaspoons Bourneville cocoa mixed to a paste with cream and 1-2g soft brown sugar. A mousse of sorts I think. Occasionally mix up some kelp powder, spirulina powder, and olive oil to a paste and eat for iodine fix. Not pleasant but miles better than iodine deficiency, which will seriously mess you up. I also use the iodised table salt. I wish someone would add the iodine supplement to unprocessed sea salt.

Calories? I dunno. One day I sort of counted and it came to 1,800, so since then I've tried to stop undereating. Carbs? Probably 50g, not often more than 100g. But all starchy carbs are eaten at the evening meal, and with plenty of fat, so the GI and insulin rise is limited. And I do notice, over time, that this has left me feeling healthier and more energetic in the evenings. I try to stay out of glycogen-depleting ketosis but well below the supposed daily requirement of 150g glucose. Actually I would find it hard to eat 150 carb grams in a day with this diet. I don't often eat potatoes or rice, and I'm sceptical that resistant starch is a type of fibre I need. I do occasionally eat small amounts of oats at the moment. I figure that my Scottish genes - and my years of abstaining from wheat and rye - are enabling me to do this with seeming impunity.

I don't usually exercise for the sake of exercising, but I do run or jump or climb or whatever because I feel like it sometimes. Walking up big hills or small mountains is probably the most energetic thing I do, and swimming in the summer. My house is up a steep drive and a few flights of steps and I run up those rather than walk the boring slow way. Instinctive exercise, like instinctive eating, is what works best for me; attempts to develop my strength capacity tend to result in avoidable injuries, and it seems to be developing satisfactorily anyway.

Supplements - vitamin D and K2, magnesium 150-300mg, vitamin C 1g, occasional probiotics, very occasional low-dose multivitamin. I'd take selenium 100-150mcg if I didn't have Brazil nuts and would supplement zinc if I could find a cheap one with no B6.

So what we have here is Atkins-type macronutrient tinkering, tweaked for the effect on microbiota. Which is like "Phase 2" of any long-term diet plan (see Art Ayer's "Cooling Inflammation" link at the right).
So what do I make of the fact that high-fat diets can produce unwanted LPS elevations in rats and humans eating their respectively standard rat and human chows?

The quality of fats is important. Extrapolations from rodent diets where fats are 30% PUFA, are all extrinsic fats, carbohydrate is still a major part of energy as pure sugar and starch, and types and amounts of fibre are limited are only relevant to similar human diets; these rat diets often resemble cheesecake recipes.
My belief is that a high-fat diet (butter, fish, eggs for cholesterol and choline) can be used to restrict bacterial overgrowth (via higher levels of bile and stomach acid) and set the scene for the right fibre and probiotics to work. Further, butter is a good source of butyrate (about 3-4%), which means 100g butter contributes about as much butyrate as 6-8g dietary fibre on a good day without the risk of a non-specific prebiotic effect. My strategy is to cook whenever possible fibrous vegetables (pumpkin, greens, sweet potato, tomato, parsnip) with butter (as you will find in French quisine) which seems to work well.

Music - Mascagni, the "octopus aria" (Aria della poivra) from Iris.

The world at large will never be convinced of the benefits of low-carbohydrate diets until the still-vilified "saturated fat" is fully acquitted of the charges falsely laid in the courts of public opinion. Butter is the poster child for the defendant saturated fat, and also the most nutritious and beneficial of the all-fat foods. So any campaign to vindicate SaFAs should begin with butter.

If anyone needs reminding why it is essential that very low carb diets enter the medical mainstream today rather than tomorrow, I recommend Toxic's post on the subject. This is incendiary stuff, and if it doesn't make you feel like fire-bombing a bakery you have no soul. Churn, butter; Henderson & Pollard Ltd; [?]; CT78.743

Churn, butter; Henderson & Pollard Ltd; [?]; CT78.743

(Minimal processing is required - you can make butter from cream at home with a jam jar and a marble)

A few weeks or months back I linked to the two studies by Mozaffarian et al. showing a protective association between dairy fat and diabetes (2010 and 2013). I pointed out that these observational studies used a more reliable measurement than the food frequency questionnaire, and that the correlation was of an order of magnitude (0.38 and 0.52) significant enough to be meaningful in the presence of plausible mechanisms. I know that some bloggers tend to completely reject dietary epidemiology, understandably given the mistaken weight given to the weakest correlations by prejudiced scientists in the media, but strong correlations imply causation, and will constitute part of the proof if causation is considered proven. Professor Feinman has written an excellent guide for the perplexed on the value of epidemiological studies in the scientific tradition, which I recommend to anyone confused about the issue.

Back when I was really sick with hepatitis and food allergies and so on, I thought I didn't tolerate fat so well. Fatty foods like icecream or creamy desserts made me throw up, and given the advice one heard, and still hears, the fat seemed the obvious culprit. But I could always eat butter without any problems, and I found it interesting that this fat, which I knew to be highly saturated, should never make me ill, indeed seemed to make me feel better. But still I took seriously, and to my shame repeated, that pernicious meme about saturated fats being bad and vegetable oils beneficial. It's called cognitive dissonance. Until one day in a spirit of inquiry - and thank God for the internet - I googled "health benefits of saturated fats", came across Mary Enig's writing on the Weston A. Price website, checked out the references, and came away a new man.

What is the fat in butter? It's the fat produced from a 100% plant-based, high-fibre diet by an animal actually designed to eat one. It's what cellulose would become in our bodies if we (or rather our microbiota) could metabolise cellulose, plus the products of other fibres, starches and sugars in the grass, silage, or other feeds, and any fatty acids therein. One of these products of fermentation is butyric acid, incorprated in triglycerides as butyrate; butyrate makes up 3-4% of butter and is also formed in the human gut when dietary fibre is fermented by the right bacteria. Most of the benefits of fibre in the diet seem to relate to the formation of butyrate, and if the bacterial species present are those that instead prefer to generate D-lactate, or high levels of propionate, the results will not be beneficial - see the section "D-lactic and propionic acid - a cautionary tale" half-way down this probiotic review.

(Sheep's milk is higher in butyrate and MCTs than cow's milk)

A popular probiotic in Japan is clostridium butyricum, which generates high levels of butyrate from dietary fibre. It turns out that these probiotics, or the butyrate derived from them, protect the liver from cirrhosis and cancer in the rat model of fatty liver disease (a diet deficient in choline and methionine - eat your eggs folks! Another demonized food that can actually save your life. In Colin T. Cambell's contentious China Study, the raw data shows a significant liver-protective effect of egg consumption). This study is a treat, full of photos and easy-to-understand graphics. It shows that even in the choline-methionine deficient rat (a huge metabolic barrier to surmount) the progression of cirrhosis and cancer is significantly slowed by butyrate (NaB).

Pharmacological studies and siRNA knockdown experiments showed that NaB-mediated AMPK activation induced the phosphorylation and nuclear translocation of Sirtuin 1, leading to the increased assembly of mammalian TOR complex 2 and phosphorylation of AKT at Ser473 and subsequent induction of Nrf2 expression and activation. These favorable changes caused an obvious decrease in hepatic fibrous deposition, GST-P-positive foci development, and hepatocarcinogenesis.

100 grams of butter, which would be about 1/3 of a day's calories, will supply 3-4 grams of butyrate and this is (roughly) as much as 6-8 grams of dietary fibre will supply under perfect conditions. The RDA says that foods that contain more than 6g fibre per 100g are considered high fibre foods, which means that butter is, in effect, a high fibre food, one where there is no risk of the fibre going to feed the wrong bacteria - it's all good. Cook some greens or other fibrous vegetables with your butter if you like, it helps to keep it on your knife, as when eating peas with honey.

(Camel's milk is the most hepatoprotective milk there is)

Here's an interesting human study showing that fat is the most important nutrient for people recovering from hepatocellular cancer (PDF). It's been couched in some technical oncologist or biophysics jargon that is mildly impenetrable, but what I get from it is this: people with cirrhosis do worse if they don't get enough energy (this is a universal finding - non-alcohol calories protect against cirrhosis progression). They tend to undereat protein, but the deficiency that has most impact on cancer recovery is fat. And the reason for this is that the metabolically damaged cirrhotic liver cannot derive energy from carbohydrate and protein with the same efficiency that it can generate ATP from fat. I can think of two reasons; a damaged liver has difficulty synthesizing co-enzymes from vitamin precursors, and the generation of ATP from carbohydrate and protein requires more variety of co-enzymes to be synthesized, and more enzymes, than the relatively simple, repetitive process of fatty acid beta-oxidation. The other reason will be familiar to regular readers of Hyperlipid; if the mitochondrial damage is mainly at Complex I, as is almost always the case for some reason, this will impede the generation of ATP from glucose (more NADH, less FADH2 generated, complex 1 handles the NADH) more than it impedes generation of ATP from fat (more FADH2 relative to NADH).
Fat, therefore, is easy on the liver, and saturated fat the easiest of all, because the simplest to metabolize. I've shown in earlier posts how saturated (and monounsaturated) fats protect the liver because of their inherent stability compared to polyunsaturated fats, passively supporting the liver's antioxidant defenses. Butter also contains fats as MCTs, up to 15%, less than coconut oil, it's a source of vitamins A, D, E, and K2 as well as carotenoids, cholesterol and CLA. I'm sure there's another post in all this, but I've written more than enough already.

If HCV up-regulates HMG-CoA reductase, yet inhibits cholesterol completion, and if low cholesterol scores are associated with both hepatocellular cancer and poor response to treatment in people with chronic HCV infection (and much the same also applies to HBV), it seems reasonable that people with these conditions will benefit from cholesterol in the diet.

(Listen to a song that deserves to be famous - Sexually Attracted to Myself by Reader's Wives)

Eggs are well known as a food high in cholesterol, and counties where the population consumed most eggs had a 0.54 OR for cirrhosis in the China Study (if that's a correct extrapolation from -46). That's a whopping decrease, and probably meaningful, and cirrhosis in China mainly relates to chronic HBV and HCV infection.
Denise Minger points out that the average egg consumption associated with these results is only equal to 2-3 eggs a week. But then, that is an average, and the statistic will include people who ate more eggs and people who ate less. Eggs not only supply cholesterol but also choline, and choline deficiency is the most efficient way to create fatty liver disease experimentally. An animal fed such a diet cannot assemble VLDL particles so both lipids (especially oleic acid, both from diet and from DNL elongation of palmitate) and cholesterol (synthesis is likely increased to try to shift the hepatic fatty acid load) accumulate, resulting in NASH, where crystallization of cholesterol in the liver is implicated. Fatty liver is pretty much the precondition for cirrhosis (5 OR), so the balance between cholesterol and choline (i.e. phospholipids) in the diet may be of importance.

File:Cholesterol.svg

A new paper has shown an association between dietary cholesterol and progression of cirrhosis in chronic HCV infection. I don't have the full text access and would love to see the raw data if anyone does have access, but in the meantime will speculate on what it means.

Dietary Cholesterol Intake Is Associated With Progression of Liver Disease in Patients With Chronic Hepatitis C: Analysis of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial.

After adjustments for age, sex, race, presence of cirrhosis, body mass index, treatment with peginterferon, lifetime alcohol consumption, smoking, health status, and coffee and macronutrient intake, each higher quartile of cholesterol intake was associated with a 46% increase in the risk of clinical or histologic progression (adjusted hazard ratio [AHR], 1.46; 95% confidence interval [CI], 1.13-1.87; P for the trend = .004). Compared with patients in the lowest quartile of cholesterol intake (32-152 mg/day), those in the 3rd (224-310 mg/day; AHR, 2.83; 95% CI, 1.45-5.51) and 4th quartiles (>310 mg/day; AHR, 2.74; 95% CI, 1.22-6.16) had significantly increased risk of disease progression.

The first thing I'm noticing is a poor dose-response relationship: the AHR from the highest quartile is slightly less than from the 3rd quartile. And the second quartile isn't available for comparison. But I'm prepared to believe for now that this effect can plateau. The second thing I notice is the number of adjustments for confounders, and no mention of the unadjusted results in the abstract. If the authors are coming from a position of prejudice (say they're vegans or similar plant-based zealots), this is where things will get tricky, But the correlation is so high I think we should give them the benefit of the doubt for now.
One confounder which is not mentioned is that individuals with the lowest cholesterol intake (it's quite hard to achieve these levels) were probably health-conscious individuals who also avoided processed food, ate plenty of fibrous vegetables, and were more likely to take vitamin, mineral and antioxidant supplements.
And another factor, one that shifts this from the ordinary, is the immune activation of long-term interferon treatment. They have adjusted for this, but the treatment may apply to all subjects, and the adjustment may be for duration, dose, numbers of treatments (correction: the HALT-C trial included a placebo arm).

Cholesterol is a nutrient, not a food. It's also a nutrient that can be damaged in the processing and preparation of food. Hopefully there will be tables in the full-text that detail the types of food that were used to calculate cholesterol consumption. The paper was published in the USA, so we can speculate about the ways cholesterol will get into the diet. From the cholesterol food charts we see that egg yolks, liver, butter, and crustaceans are high in cholesterol. Other common foods like meats and milk are lower but may be consumed in higher quantities. From this data (table 1) we see that pork can be rich in cholesterol. Pork offal used in sausages and processed meats must be especially so.
Americans do not eat large amounts of butter these days on a per capita basis, nor do they eat much seafood. Egg yolks are perhaps most likely to be consumed in baked goods and mayonnaise, perhaps even powdered eggs. What will also be consumed on a daily basis is meat, pork, chicken skin, and processed meat products, and also flavoured milk, whipped cream and other dairy products.
Is there any food on this list that already has a strong association with cirrhosis?

Pork does. The consumption of pork, and especially pork offal, is strongly associated with alcoholic cirrhosis across countries and counties, and in this "clinical microcosm" study.

1998 Nov;22(8):1803-5.

Effect of the type of beverage and meat consumed by alcoholics with alcoholic liver disease.

Bode C, Bode JC, Erhardt JG, French BA, French SW.

Source

Institut für Biologische Chemie and Ernährungswissenschaft, F.B., Ernährungs Physiologie, Universität Hohenheim, Stuttgart, Germany.

Abstract

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.

There is also a correlation between pork and hepatocellular cancer which is quite strikingly independent of alcohol consumption in table 1 of this PDF.

I will not go into the pork data in detail because Paul Jaminet has already done so, in a series of 3 articles beginning here.

"Pork consumption has a strong epidemiological association with cirrhosis of the liver. Startlingly, pork may be even more strongly associated with alcoholic cirrhosis than alcohol itself!

The evidence was summarized by Francis Bridges in a recent (2009) paper [1], building on earlier work by Nanji and French [2]. A relation between pork consumption and cirrhosis of the liver is apparent across countries and has been consistently maintained for at least 40 years."

I'm not certain that the explanation Paul prefers (hepatitis E) completely explains the correlation, I still consider this a mystery for the ages. I did come across a possible explanation today which, though speculative, appeals to me.

Yersinia enterocolitica is a common bacterial contaminant of pork, especially ground pork, which is destroyed by cooking.

("Yersiniae are usually transmitted to humans by insufficiently cooked pork or contaminated water.")
It causes a nasty but self-limiting gastrointestinal syndrome, and can migrate to the liver, causing abscesses. But the most intriguing thing is a link between y. enterocolitica and arthritis. ("Y. enterocolitica infections are sometimes followed by chronic inflammatory diseases such as arthritis."). Or fibrosis? Arthritis is a disease with a great deal in common with hepatic fibrosis, it involves similar inflammatory pathways and cellular processes and the same anti-inflammatory compounds are useful in both conditions. What if cirrhosis is promoted, not necessarily by infection with y. enterocolitica, but by exposure to the killed bacteria in cooked meat? In a leaky gut scenario (and IBO is also associated with cirrhosis), LPS that is present in the meat (or an exotoxin, or antigen, or YopP) finds its way to the liver and much the same immune reaction that causes arthritis eventuates there. Well it's a theory, and I really mention it as an example of the kind of thing that might be going on.

Stop Press: yersinia enterocolitica YOP antibodies are found in 20-25% of population, with higher incidence in autoimmune thyroiditis. YE is found in ascitic fluid of cirrhotics, especially alcoholic cirrhosis. Persistent asymptomatic YE infection, with potential for post infection autoimmune sequelae, seems to be relatively common.

Interestingly, dietary cholesterol (and saturated fat) are actually associated with protection from alcoholic cirrhosis, so it doesn't seem to be the cholesterol in the pork per se that makes it problematic.

So far, cholesterol might be harmful in the presence of fatty liver and choline deficiency, or it might be a marker for the harmful food pork. There is also the question of oxidized cholesterol. Cholesterol in food is oxidized by long cooking, drying, or high temperatures. You don't want the cholesterol in your bloodstream to become oxidized, this is a risk factor for atherosclerosis, so you probably want to keep that in your food fresh too (I find the science around this a little fuzzy, but why not). With eggs and butter, this is easy as very little cooking is needed; with meat it is harder (especially given the presence of pathogens). Slow cooking at low temperatures is probably the way to go, and especially boiling in water - stews and soups - where temperature is limited by the evaporation of the water as it heats.

I eat about 2 eggs a day, plenty of butter. I rarely eat offal, and it's either lamb kidneys or chicken liver, eaten instead of eggs. Maybe once a week. My cholesterol intake is definitely in the upper quartiles (and probably always has been, at least when I've been healthy enough to eat well). I also have occasional low-cholesterol, higher carbohydrate days when I will eat smaller amounts of sushi or stir-fry instead of my usual food. I figure this helps my gall bladder flush any extra, unwanted cholesterol it's holding, because we can't necessarily expect the enterohepatic circulation to work perfectly all the time. I eat bacon (which seems to be the least problematic form of pork immunologically) because it is so damn convenient and digestible, and probably have pork chop or mince once a week. I avoid most sausages, and all other processed meats. If my liver histology ever shifted in the direction of fibrosis (fibroscan still shows "mild scarring" after many decades of chronic self-abuse and HCV infection, some years more enjoyable than others), I would cut pork products completely as my first option. I would hate to move from eating butter to depending on some processed empty-calorie food like coconut oil. Butter has a cholesterol/choline ratio of 10:1, whereas egg yolk and chicken liver have a ratio of 2:1. Nuts, legumes and leafy vegetables are also supplying smaller amounts of choline. Cirrhosis is, almost always, a sequel to fatty liver disease, and a diet high in choline and saturated fat and low in carbohydrate and polyunsaturated fat will reverse fatty liver disease. I'm going to take a watching brief on this issue. I might consult this doctor:

"He knew, from many distinguished examples, how easily such a thing can become a mania, and how the most sober and balanced of men, once this passion is upon them, can lose completely their sense of proportion and spend years in trying to establish a particular theory the evidence for which could be written upon a postcard."
I remember this passage, from Iris Murdoch's "The Flight from the Enchanter", every day, and especially when I receive information that may cause me to modify my hypothesis.

Reading up on cholesterol with regard to Dr Yu's study that I discussed in my last post (a study of chronic hepatitis C cases, non-responders, showing increased progression of fibrosis and cirrhosis with higher cholesterol intakes), it becomes quite obvious that cholesterol should have a role in fibrosis and cirrhosis.

Apt tune; Rufus Wainright, Cigarettes and Chocolate Milk

You can cause fatty liver in an animal with a variety of strategies; a methionine-choline deficient diet, alcohol plus linoleic acid, a high fat diet (unless the fat is butter or coconut oil, or the animal is intermittently fasted); or fructose plus linoleic acid. The latter two are models of NAFLD (non-alcoholic fatty liver disease). NAFLD can progress to NASH, non-alcoholic steatohepatitis, an inflammatory disease which results in fibrosis and cirrhosis.
What is needed to turn NAFLD into NASH in rodents? Dietary cholesterol. 1% (which is a lot).
What happens if cholesterol is added to the alcohol-linoleic acid (or indeed fish oil) model of alcoholic liver disease?

In rats given intragastric ethanol and either corn or fish oil,
addition of cholesterol (1%) does not change the degree of
fatty infiltration but prevents hepatic necrosis and inflammation
and enhances hepatic fibrosis. Cholesterol in this model
decreases the enhanced low-density lipoprotein receptor
message, eliminates messages for TNF-a and COX-2, and
decreases plasma and liver levels of thromboxane B2, and
products of lipid peroxidation, whereas it increases transforming
growth factor-b message. The anti-inflammatory effects of
cholesterol are most likely related to a decreased uptake of
arachidonic acid caused by downregulation of the low density
lipoprotein receptor and its decreased conversion to
eicosanoids via decreased COX-2 activity. Enhanced fibrosis
may be mediated by increased transforming growth factor-b.

(TGF-beta being a signal that activates hepatic stellate cells).

What happens in a non-alcohol model?

Livers of DD-fed mice showed histological changes resembling NAFLD, including steatosis and modest fibrotic changes; however, DDC-fed animals developed micro- and macrovesicular steatosis, inflammatory cell foci, and fibrosis resembling human NASH. Dietary cholesterol also exacerbated hepatic macrophage infiltration, apoptosis, and oxidative stress.
Dietary cholesterol appears to confer a second “hit” that results in a distinct hepatic phenotype characterized by increased inflammation and oxidative stress.

What sorts of factors that set the stage for a NASH-like syndrome might be present in HCV patients?
(Note that HCV fibrosis differs from NASH in that it is spread more evenly through the liver, consistent perhaps with an intracellular causative agent).
The NAFLD diet above is described as "diabetogenic", and NAFLD is associated with diabetes, obesity, and metabolic syndrome. The animal diets that cause it and predispose to NASH require the same nutrients that, frankly, cause diabetes and NAFLD in humans. Seed oils, lard, and refined carbohydrates that are predominantly sugar (also fish oil, but only in doses that no-one ever ate). Round the clock feeding and overfeeding. Factor in HCV, which is diabetogenic in its own way and (Genotype 3) promotes steatosis (incidentally, Genotype 3 does the most to depress cholesterol completion, and would logically benefit most from dietary cholesterol were the NASH issue moot).
Another point that might be of major importance to humans is the n-6:n-3 ratio.

Introduction and aim: Essential dietary polyunsaturated fatty acids (PUFA) include omega-6 (n-6) linoleic acid (18:2) which is metabolized to arachidonic acid (AA) and omega-3 (n-3) linolenic acid (18:3) which is metabolized to eicosapentanoic acid (EPA). Imbalance in secondary eicosanoids and prostaglandin metabolites of n-6 and n-3 PUFA are implicated in disorders related to the metabolic syndrome. Skeletal muscle PUFA influences systemic insulin sensitivity (Borkman 1993) and diets rich in omega-3 fatty acids are associated with diminished histological injury in NASH (Musso 2003). Erythrocyte membrane lipids reflect dietary intake of essential fatty acid over preceding months. We measured erythrocyte n-6:n-3 ratio in a cohort of patients as part of a larger study of omega-3 fatty acid therapy of NASH.
Methods: 15 patients (10 female) underwent analysis of erythrocyte lipid composition using capillary gas chromatography (Metametrix, Duluth, GA) to determine the AA:EPA ratio. The mean age was 50 ± 13 years all with liver biopsy NAS score ≥ 5 and a range of non-cirrhotic fibrosis stages of stage 1 (n = 6), stage 2 (n = 5) and stage 3 (n = 4).
Results: The mean AA:EPA was 65 ± 34 reflecting a relative excess of n-6 PUFA overall. However, a broad range was noted from 15 to 144 AA:EPA. Dividing the group into quintiles of the reference range, 9 of the patients fell into the highest (5^th) quintile (AA:EPA = 84 ± 30) compared to the remaining 6 patients (AA:EPA = 36 ± 16, p = 0.001). There was no statistically significant difference in the histological stage between these groups (fibrosis score = 2 ± 0.9 versus 1.7 ± 0.8) although the higher AA:EPA group was significantly older (55±12 versus 39±12, p=0.01).
Conclusion: There is heterogeneity of AA:EPA in non-cirrhotic NASH patients and an age-related increase in n-6 to n-3 PUFA evident in the AA:EPA ratio of erythrocyte lipids. Further work is needed to understand if this reflects dietary differences and how this might influence response to omega-3 fatty acid therapy.

There is a 2012 review of Omega-3 interventions in NAFLD/NASH here.

If I might digress for a moment, I came across 2 very interesting epidemiological papers about age-related macular degeneration (AMD). Both identified linoleic acid as a factor promoting the disease, and a protective effect of fish oil and fatty fish - but this protective effect was only seen in those subjects with the lowest intake of linoleic acid:
Higher intake of specific types of fat--including vegetable, monounsaturated, and polyunsaturated fats and linoleic acid--rather than total fat intake may be associated with a greater risk for advanced AMD. Diets high in omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid was low. Conversely, neither omega-3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake.

Note that this first paper distinguished between vegetable and animal fats and only found a harmful association with vegetable fats. The second paper combined all fats:

Saturated, monounsaturated, polyunsaturated, and transunsaturated fats increased the likelihood of progression (RR, 2.09 and P trend =.08; RR, 2.21 and P trend =.04; RR, 2.28 and P trend =.04; RR, 2.39 and P trend =.008, respectively). Higher fish intake was associated with a lower risk of AMD progression among subjects with lower linoleic acid intake. Processed baked goods, which are higher in some of these fats, increased the rate of AMD progression approximately 2-fold, and nuts were protective.

Note that nuts were protective against a linoleic acid mediated disease. I hope the significance of that is not lost on you!

Well here we have someone eating a standard western diet, lots of refined starches, sugars and omega 6 oils.
They decide to throw in a bit of cholesterol, say a bacon burger and an egg McMuffin, and their NAFLD is more likely to turn to NASH.

What about people with chronic HCV infection?

2005 May;100(5):1091-8.

Factors associated with the presence of nonalcoholic steatohepatitis in patients with chronic hepatitis C.

Solis-Herruzo JA, Pérez-Carreras M, Rivas E, Fernández-Vázquez I, Garfia C, Bernardos E, Castellano G, Colina F.

Source

Departments of Gastroenterology and Pathology, Hospital Universitario Doce de Octubre, Madrid, Spain.

Abstract

OBJECTIVES:

The aim of this study was to identify factors associated with the presence of nonalcoholic steatohepatitis (NASH) in patients with chronic hepatitis C (CHC).

METHODS:

We studied 98 patients with CHC [47 with NASH (group HCV/NASH), 51 without NASH (group HCV)] and 85 with NASH not infected with hepatitis C virus (HCV) (group NASH). We determined factors associated with the presence of NASH in patients with hepatitis C.

RESULTS:

Group HCV/NASH patients resembled those with NASH. Body mass index (BMI) was higher in group HCV/NASH than in group HCV, but was similar to group NASH. Most HCV/NASH patients had risk factors for NASH. In patients infected with HCV, NASH and NASH-related lesions were independently associated with BMI, while steatosis score was associated with HCV genotype 3 and BMI. Fibrosis stage was independently associated with steatosis, necroinflammatory activity index, and NASH lesions.

CONCLUSION:

While HCV genotype 3 infection and BMI are associated with the presence of steatosis in CHC, BMI is the only factor independently associated with the presence of NASH in these patients. We suggest that overweight-related factors might induce NASH in CHC patients.

When Ned Kock re-analysed the Bridges data he came to this conclusion:

What the results summarized in this post do suggest is that pork consumption may not be a problem at all, unless you become obese from eating it. How do you get obese from eating pork? Eating it together with industrial foods that are addictive would probably help.

It looks like Ned was right, after all.

It's worth remembering what Bridges, Nanji and French did with the pork data. They didn't make a big case of it in the media and try to demonize pork. Instead they hypothesized about causes and developed animal models for testing the role of PUFAs in alcoholic liver disease. The result is the body of research that tells us - with a clarity that is unusual in diet-health science - that high-PUFA diets promote alcoholic liver disease, and highly saturated fats protect against it. French summarizes his conclusions here in a response to a paper by Amin A. Nanji called "Dietary saturated fatty acids: a novel treatment for alcoholic liver disease".

French indicates that more than 1.5% calories from PUFA will promote liver damage while an alcoholic is drinking (at least at a standard 35% fat diet), while the use of lecithin (or presumably fish oil) may be safe during recovery.

In summary, any therapeutic trial for the treatment

of ALD should be predicated on a rationale based on

experimentally shown efficacy. Using such guidelines,

the use of the feeding of dietary fats, such as palm oil,

other fats low in polyunsaturated fatty acids, or linoleic

acid, should benefit patients with ALD in the alcoholic

withdrawal phase of alcoholic hepatitis. However, to pre-

vent further liver damage during periods of alcohol abuse,

fats that contain substantial linoleic acid or polyunsatu-

rated fats should be avoided. This is because any fat

ingested that provides more than 1.5 % of dietary calories

may permit liver damage induced by alcohol to be mani-

fested. At least this is true in the growing male rat that

is fed ethanol by intragastric tube. Palm oil used by

Nanji et al. contained 8% linoleic acid, which in the

case of the rat model of ALD would not be expected to

protect the liver from injury when ethanol is ingested.

Likewise, this would also be true if patients with ALD

were treated with soybean lecithin supplements if they

continued to drink because soybean lecithin is very rich

in linoleic acid. Of course, there is a danger in extrapo-

lating animal data to humans. For instance, a diet rich

in saturated fat may have negative side effects such as

worsening cardiovascular disease in humans. Because of

this potential danger, caution should be exercised if the

animal data are to be used as rationales for the treatment

of patients with alcoholic hepatitis.

Well, thank goodness we don't need to worry about that any more.

So to summarize, high levels of cholesterol in the diet may be harmful to persons with fatty liver disease, especially in persons with chronic HCV and high BMI, unless they are in a diet designed to clear a fatty liver.
Even then, there may well may be a brief transition period in which it may be wise to limit cholesterol. Exactly how much, I haven't a clue.

I thought I would summarize my thoughts about how a diabetogenic diet causes hepatic fibrosis and how the risk is increased by high intakes of dietary cholesterol in reasonably easy-to understand language.

(music: Gary McFarland's 1969 cover of The Beatles' Get Back)

Here is the relevant part of the abstract from Dr Yu et al's paper (the full text is still behind a paywall):

After adjustments for age, sex, race, presence of cirrhosis, body mass index, treatment with peginterferon, lifetime alcohol consumption, smoking, health status, and coffee and macronutrient intake, each higher quartile of cholesterol intake was associated with a 46% increase in the risk of clinical or histologic progression (adjusted hazard ratio [AHR], 1.46; 95% confidence interval [CI], 1.13-1.87; P for the trend = .004). Compared with patients in the lowest quartile of cholesterol intake (32-152 mg/day), those in the 3rd (224-310 mg/day; AHR, 2.83; 95% CI, 1.45-5.51) and 4th quartiles (>310 mg/day; AHR, 2.74; 95% CI, 1.22-6.16) had significantly increased risk of disease progression.

Notice there is no real difference between the 3rd and 4th quartiles (the second quartile isn't mentioned, but the incremental figure of AHR 1.46 is close enough to what it must be). People who ate the most cholesterol (4th quartile) actually had the same risk of cirrhosis as people who ate a lower amount (3rd quartile). There was a limit to the increased risk. Normally a broken dose-response relationship like this would ring alarm bells, but we are talking about cholesterol, and if dietary cholesterol intake is high enough, the liver's production is inhibited. So it seems to me plausible that the effect is more or less plateaued at high intakes, and this implies that endogenous cholesterol production is also implicated.

A diet high in polyunsaturated fats increases cholesterol production by the liver (because it lowers serum cholesterol), and a high-carbohydrate diet (esp sugar, or excess starch) also increases the liver's cholesterol production (because it increases triglycerides which need to be packaged with cholesterol). If the liver is fatty, not only the fat but also the extra cholesterol will be retained in the liver. If there is also cholesterol in the diet, this increases the load, and eventually makes inner mitochondrial membranes (cristae) deformed (cristae need to expand and contract in response to energy requirements; the consequent rearrangement of the various enzyme complexes regulates their activity; cholesterol is a stiffening agent that regulates the fluidity and integrity of membranes), so the cholesterol-laden mitochondria find it hard to produce energy or clear substrates, make more free radicals, and precipitate fibrosis.

(This image shows how the accumulation of unesterified cholesterol deforms the membranes of red blood cells in patients with liver disease. Cholesterol is mostly esterfied by taurine and glycine, which are protective against fibrosis).

This is what I think happens. It could happen without dietary cholesterol, is two and a half times more likely to happen with high intakes of it - but depends on a diet that produces fatty liver, plus in this case a virus that promotes similar changes - the dietary cholesterol then being the last straw. In the context of a diet and lifestyle that is protective against fatty liver, dietary cholesterol ought not to be an issue.

Lowering free cholesterol by esterification with taurine is a rational treatment for NASH:

2006 Dec;51(12):2225-34. Epub 2006 Nov 2.

The restorative effect of taurine on experimental nonalcoholic steatohepatitis.

Chen SW, Chen YX, Shi J, Lin Y, Xie WF.

Source

Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.

Abstract

Our objective was to explore the restorative effect of taurine on experimental nonalcoholic steatohepatitis (NASH). Thirty-six SD rats were randomly divided into three groups, 12 in each group: the normal group was fed standard rat diet; the model group and the treatment group were both fed a high-fat rat diet for 12 weeks, and the rats in the treatment group were simultaneously injected with taurine subcutaneously for 8 weeks. Hepatic histological change was observed; TNF-alpha and TGF-beta(1) protein expression was identified by immunohistochemistry; mRNA expression of TNF-alpha, TGF-beta(1), type I procollagen, and adiponectin was measured by RT-PCR; body weight, weight gain, liver weight, and liver index were measured; and biochemical parameters monitored included serum transaminases, serum lipids, fasting plasma glucose, and hepatic level of oxidative stress. Rats in the model group showed a significant increase in liver weight, liver index, serum transaminase activities, serum triglyceride, fasting plasma glucose, and oxidative stress; the mRNA expression of TNF-alpha, TGF-beta(1), and type I procollagen increased, whereas the expression of adiponectin decreased significantly, compared with that in the normal group. The typical hepatic lesions of NASH were observed histologically in the model group. Taurine treatment resulted in a significant decrease in liver weight, liver index, serum transaminase activities, serum triglyceride, fasting plasma glucose, and oxidative stress; the mRNA expression of TNF-alpha, TGF-beta(1), and type I procollagen decreased, but the expression of adiponectin increased significantly, compared with that in the model group. Histological improvement was observed in the treatment group. In conclusion, taurine could inhibit lipid peroxidation, improve lipid and glucose metabolism, decrease synthesis of TNF-alpha and TGF-beta(1), promote synthesis of adiponectin, and have a restorative effect on experimental NASH.

Deeply deranged, they said.

From this paper: "Hepatic cholesterol accumulation is driven by a deeply deranged cellular cholesterol homeostasis, characterized by elevated cholesterol synthesis and uptake from circulating lipoproteins and by a reduced cholesterol excretion."
This is what happens when simple fatty liver becomes NASH, with progression of fibrosis and cirrhosis.

I commented at the time "elevated cholesterol synthesis = high PUFA diet lowering serum cholesterol and upregulating LDL receptors (lower serum cholesterol= more intracellular cholesterol), also excess sugars > TG especially with choline deficiency.
Reduced cholesterol excretion = low esterification due to deficiency of taurine, glycine, also Mg+, esp. with choline deficiency."

The first part of that is based on the mechanical function of cholesterol as a membrane-stabilising agent . Extra PUFA in cell membranes demands extra cholesterol be produced by, and much retained by, the liver. Serum cholesterol may go down (the supposed "good" result), but the NASH example shows that serum cholesterol readings are in fact a very weak and misleading indicator of intracellular disease processes involving cholesterol.
You can have "low cholesterol" while accumulating cholesterol is killing you in a much more sure and certain way than via any "lipid hypothesis" mechanism, and this might also apply to cells outside the liver in the presence of fatty liver disease.

(ew - soy oil)

The excellent Suppversity blog yesterday analysed a recent paper that shows this happening with regard to the feeding of soy oil to Wistar rats.
http://suppversity.blogspot.co.nz/2013/08/high-fish-soy-lard-low-fat-diets-how-do.html

Compared to lard-fed rats, or low-fat rats, the soy oil-fed rats had slightly lower serum cholesterol. As we tend to see in humans. But hepatic cholesterol was doubled (even though lard is a source of dietary cholesterol, and soy oil isn't). Hepatic NEFA (non-esterified fatty acids) were also doubled. This is a sure sign of trouble, more so than the elevated liver triglycerides.

(Picture borrowed from Suppversity blog and based on Hashimoto et al. 2013)

The other interesting thing was the generally beneficial picture seen with fish-oil feeding. Combined with alcohol, fish oil is deadly to the liver. Granted the fish oil effects were extreme, reflecting the enormous dosage, and perhaps undesirable in other ways, such as depressed immunity, but fish oil wasn't causing fatty liver or predisposing to NASH in this model.

It's all about omega 6. And, I suspect, about linoleate, not arachidonic acid.
This was 45% energy from soy oil, which (edit) was about 50% linoleate (a bottle I saw today was 58% PUFA). If your hepatic cholesterol is increased, and you also eat foods high in cholesterol, the liver isn't going to cope with that extra cholesterol, is it? It's already struggling with its own production.

So the very "food" you consume to help with your imagined cholesterol problem can be causing a very real and lethal cholesterol problem. Unless that food is fish. Or nuts, for a different, complicated and somewhat obscure reason, probably not much to do with linoleate.

To start with the latest on the story of linoleic acid and cholesterol, NAFLD and NASH; this PDF
Effects of dietary cholesterol and fatty acids on plasma cholesterol level and hepatic lipoprotein metabolism
sets out what I think might be the "design flaw" in hepatic cholesterol regulation. Cholesterol is the only lipid I can think of which is produced through the TCA cycle but cannot be broken down again by beta-oxidation and the TCA cycle - it has to be conjugated and excreted. Thus the medical focus on cholesterol and disease is not, of itself, a deluded one. It is the focus on saturated fat and serum cholesterol that is 100% deluded. (Uffe Ravnskov lays out the facts about that in what should really be "enough already" style here)
Anyway:
As hepatic cholesterol increases, HMG-CoA reductase is downregulated to maintain homeostasis. But when intake of linoleate is high, hepatic LDL receptors are upregulated, increasing hepatic cholesterol uptake, and if dietary cholesterol is also high, perhaps HMG-CoA reductase downregulation is insufficient to cope, especially if taurine (which conjugates and removes free cholesterol) is insufficient. In the words of the paper:
There is a discrepancy in the regulation of HMG-CoA -reductase and LDL receptor activities in liver from animals fed cholesterol with linoleic acid. In spite of a high content of hepatic cholesterol and obvious suppression of hepatic HMG-CoA reductase activity, the hepatic LDL receptor activity was rather increased in animals fed cholesterol with linoleic acid in comparison with control animals (Tables 4 and 5, Fig. 1). This result suggests that fatty acids, especially linoleic acid, independently influence the regulatory pathway of LDL receptors and HMG-CoA reductase activity by cholesterol.

The situation is further complicated by the fact that carbon from linoleic acid goes into the synthesis of other lipids - including cholesterol and palmitate. And this is consistent with another feature of NAFLD - increased rates of lipolysis and DNL, and a 2x greater flux through the TCA cycle, futile cycling which does not clear the liver of fat, but rearranges lipid carbon instead. We might hypothesise that the linoleic acid is potentially so destabilising that any excess automatically goes to make more rigid lipids, but that where there are insufficient factors to neutralise these lipids (such as taurine or CYP esterification pathways for free cholesterol, or oleic acid to promote the inclusion of palmitate in triglycerides - interesting sideline here is that high-oleic acid diets might encourage the "safe" and stable form of fatty liver), or to oxidise them (because of preoccupation with oxidising carbohydrate), they accumulate in the toxic free state. We might also observe that diets very rich in both cholesterol and linoleate are quite rare in nature, omnivores tend to substitute nuts and seeds for meat when either is less available.

But perhaps the problem does not lie with nuts and seeds at all. Perhaps, in the case of humans, who probably don't consume large amounts of soy or corn oil except in cooking, the problem is with peroxides from heated linoleate - what Bill Lagakos called "molested fats".
Finally someone has sought to answer the question of what these peroxides might do to the liver.
I don't have full-text access yet but luckily the Journal of Hepatology provides both abstract and editorial comment:

In order to test the hypothesis that peroxidized fatty acids, generated by heating of standard cooking oils, trigger hepatic inflammation, Boehm et al. performed short-term experiments in which they heated standard corn oil to raise peroxide content more than 100-fold compared to unheated oil and gavaged rats with either standard or heated corn oil for six consecutive days. The livers of animals treated with heated corn oil expressed higher levels of several inflammatory genes, including interleukin 1beta, cyclooxygenase-2 (COX-2), and tumor necrosis factor alpha. This was associated with increased infiltration of CD68 positive macrophages. Peroxidized linoleic acid induced nitric oxide synthase-1 and COX-2 in Kupffer cells and mixed non-parenchymal cells through activation of p38 MAP kinase pathway. Whether these findings are relevant to human disease remains to be determined.

Background & Aims

Obesity and hepatic steatosis are frequently associated with the development of a non-alcoholic steatohepatitis (NASH). The mechanisms driving progression of a non-inflamed steatosis to NASH are largely unknown. Here, we investigated whether ingestion of peroxidized lipids, as being present in Western style diet, triggers the development of hepatic inflammation.

Methods

Corn oil containing peroxidized fatty acids was administered to rats by gavage for 6

days. In a separate approach, hepatocytes (HC), endothelial (EC) and Kupffer cells (KC) were isolated from untreated livers, cultured, and incubated with peroxidized linoleic acid (LOOH; linoleic acid (LH) being the main fatty acid in corn oil). Samples obtained from in vivo and in vitro studies were mainly investigated by qRT-PCR and biochemical determinations of lipid peroxidation products.

Results

Rat treatment with peroxidized corn oil resulted in increased hepatic lipid peroxidation, upregulation of nitric oxide synthetase-2 (NOS-2), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNFα), elevation of total nitric oxides, and increase in cd68-, cd163-, TNFα-, and/or COX-2 positive immune cells in the liver. When investigating liver cell types, LOOH elevated the secretion of TNFα, p38MAPK phosphorylation, and mRNA levels of NOS-2, COX-2, andTNFα, mainly in KC. The elevation of gene expression could be abrogated by inhibiting p38MAPK, which indicates that p38MAPK activation is involved in the pro-inflammatory effects of LOOH.

Conclusions

These data show for the first time that ingestion of peroxidized fatty acids carries a considerable pro-inflammatory stimulus into the body which reaches the liver and may trigger the development of hepatic inflammation.

edit: from the fulltext (Thanks Bill):The present data suggest that the ingestion of peroxidized linoleic acid is much more effective than the unperoxidized form in evoking pro-oxidant and pro-inﬂammatory processes in the liver, i.e., native linoleic acid induced shedding of TNFa from the cell surface but failed to signiﬁcantly alter intracellular mRNA levels of classical pro-oxidant and pro-inﬂammatory genes. According to these ﬁndings, it has to be considered that increased uptake of lipid peroxidation products, as occurring with unhealthy eating habits, may contribute considerably to the generation of sparks igniting hepatic inﬂammation. Thus, further studies in humans are urgently required to check for a causal link between ingestion of lipid peroxides and emergence of NASH.
(Comment; knowing how significant the effect of unheated corn oil is already in animal liver inflammation models, this is some interesting news. Consider the pork-cirrhosis link again; pork is not only high in both cholesterol and linoleic acid, it needs to be eaten well-cooked)

So this allows us to construct a likely hierarchy of linoleate sources; best are nuts and seeds, next best are 11% oils like olive oil, more harmful are oils like rice bran and canola, worse still are soy, corn, sunflower and safflower oil, and worst of all? French fries and fish and chips, donuts and baked goods, and so on.

Just to prove that food quality matters in the care of chronic hepatitis C, here's a study that shows that even a low-fat diet, or a (somewhat) calorie-restricted diet, will produce some benefit in over-weight Hep C patients if food quality and exercise are put first; increased intake of olive oil, nuts, vegetables, fruit, wholegrains, increased exercise, and decreased intake of refined and processed carbohydrate, limited cholesterol and saturated fat. Which in the context of the Bulgarian diet might have meant less fried food.

Effects of lifestyle changes including specific dietary intervention and physical activity in the management of patients with chronic hepatitis C – a randomized trial

I think you would get these results quicker with a low-carb diet if you paid as much attention to food quality and exercise, and you would see more benefits in terms of quality of life and extrahepatic syndromes, but the important thing is that food quality trumps all, and even makes calorie restriction and fat restriction tolerable (if it was as great as reported).
File:Rhodope Mountains Bulgarian food 04.JPG

Lastly, a long-overdue link to It'sthewooo's probiotic series. Part 1 Part 2 Part 3 I recommend taking probiotics, but I haven't gone into the details much because I see it as something of a personal quest and complicated. Reading someone else's honest description of their findings is a good way to prepare yourself, or compare your results, and Woo is the model of a reliable guide here. And generally a most interesting and entertaining blogger. Someone faulted Woo for not providing many references for her claims, I considered this, and actually couldn't remember a time when she'd been wrong about some statement of medical nous. People can and should do their own research, links are a courtesy, when you're say, a nurse like Woo, and have to know stuff because you've been taught it, and see the truth of it every day, pulling up references for everything is a little infra dig.
If I don't give a link for everything, look it up yourself and prove me wrong. And where I do give a reference, that may be mistaken anyway, or misinterpreted by me, so people who really want to engage with the science, should develop the habit of questioning it. Anyone worth listening to and still engaged in learning is modifying their opinion all the time.

Peter D has been running a fantastic series on PUFAs and cancer. Lots of references to linoleic acid promoting the growth of hepatoma cells.

"In the lab situation rapid hepatoma tumour growth needs either arachidonic or linoleic acids. The acids must be taken up in to the hepatoma cells, they must be acted on by lipoxygenase to produce 13-hydroxyoctadecadienoic acid, better known as 13-HODE. 13-HODE appears to be the mitogen which promotes rapid cancer growth. 13-HODE looks like a repair signal gone wrong in cancer cells."

Wonderful stuff in line with all the other deleterious effects of excess (seed oil amounts) of linoleate on liver function, and with the benefits of omega 3's.

This passage also caught my eye:
"omega 3 fatty acids, in a G-protein coupled receptor manner, completely turn off the uptake of ALL fatty acids in to hepatoma cells. If, and it's quite a big "if", the same effects apply to hepatocytes as well as hepatoma cells, we then have a very straightforward mechanism for the protective effects of omega 3 fish oils on hepatic lipidosis."
(or for that matter, steatosis).

This interests me because, in Hep C research, HCV can only be cultured in hepatoma cells. You can't culture it in normal hepatocytes. And this provides an answer to an old question - why do viruses cause cancer? What's the benefit, given the risk of killing the host? Because, there is something about the cancer phenotype of a cell that makes the cell a better host to the virus. Obviously it doesn't want to push carcinogenesis all the way (which is why only a small minority of chronic HCV cases end up as HCC), but it does want to tweak the cell a little in that direction. Hence activities like sequestering selenium. Better not give that virus-infected cell too much linoleate to play with.

In the middle of this discussion, Purposelessness dropped this 2008 mouse paper:

cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids

This is great science thinking about the obesity epidemic. Why are high-carb diets only generally productive of obesity when linoleate is added, and not, say, in Kitava (where most fat comes from coconut and some from fish?). If it's the linoleate, how come low-carb dieters loose weight on cupfuls of nuts and olive oil - or even canola oil - with everything?

The effect of dietary fat on human health is not solely a matter of quantity but depends also on the nature of the fatty acids. The current recommendation is to replace saturated fat by polyunsaturated fatty acids (PUFAs).⁵ Today, more than 85% of the total dietary PUFA intake in Western diets is n-6 PUFAs, mainly linoleic acid, a precursor of arachidonic acid, whereas the consumption of n-3 PUFAs has declined (1). Since the high intake of n-6 has been associated with childhood obesity, concerns regarding this matter have been raised (2). However, animal studies have yielded conflicting results, with some studies demonstrating that a diet enriched in n-6 PUFAs decreases adipose tissue mass (3, 4), whereas others have associated intake of n-6 PUFAs with an increased propensity for obesity (5-7).

So, we have a paradox. And a solution.

In the present study, we present data that reconcile and explain the disparate effects of n-6 PUFAs on adipocyte differentiation in vitro and in vivo. We demonstrate that cAMP signaling plays a pivotal role controlling the production of antiadipogenic prostaglandins. In vivo, the obesigenic action of n-6 PUFAs is determined by the balance between dietary carbohydrates and protein. A high carbohydrate/protein ratio translated into a high plasma insulin/glucagon ratio, and in this setting, dietary n-6 PUFAs promoted strongly adipose tissue expansion. Conversely, a high protein/carbohydrate ratio translated into a high plasma glucagon/insulin ratio and enhanced cAMP-dependent signaling. In this setting, COX-mediated prostaglandin synthesis was enhanced, and dietary n-6 PUFAs decreased white adipose tissue mass.

Don't try this last bit at home; those prostaglandins might not be liver-friendly, but you can do much the same job with omega 3s.

This bit is for all the calorie nerds:

The decreased obesigenic action ofn-6 PUFAs in mice fed a protein-rich diet did not result from increased dissipation of energy by uncoupled respiration but rather reflected increased energy expenditure in relation to gluconeogenesis and urea formation.

Phew, we didn't break the laws of thermodynamics, so the CICO police are not after us.

We observed a remarkable difference in feed efficiency between mice fed the protein-enriched versus the carbohydrate-enriched diet. In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues. Increased cAMP signaling is known to induce adaptive thermogenesis by inducing expression of PGC-1α and UCP1 in brown adipose tissue (30), but the fact that heat production and oxygen consumption as well as expression of UCP1 in intracapular brown adipose tissue were similar in the two groups of mice indicated that decreased feed efficiency of the protein group was not due to increased uncoupled respiration. Furthermore, no increase in genes involved in fatty acid oxidation in muscle and liver was observed in the mice fed the protein-enriched diet, and the total physical activity of the carbohydrate and the protein group did not differ. Expression of UCP1 and genes involved in β-oxidation was, however, induced in the inguinal fat pad, but the relatively low expression of these genes compared with interscapular brown adipose tissue suggested that such a contribution to whole body metabolism was limited.

Oh no, not DNL too, I though that was all debunked, sorry folks

A hallmark of PUFA action is the ability to increase catabolism by enhancing ketogenesis and peroxisomal and mitochondrial fatty acid oxidation and to suppress expression of genes involved in lipogenesis in rodents (36). It is worth noting that the hepatic expression of rate-limiting enzymes involved in fatty acid catabolism was similar in mice fed corn oil supplemented with protein and sucrose. In contrast, expression of genes involved in lipogenesis was significantly lower in liver of mice fed corn oil and protein compared with corn oil and sucrose. Thus, despite high dietary intake of fatty acids, expression of genes involved in de novo synthesis of fatty acid continued when dietary corn oil was combined with sucrose.

In conclusion:

In conclusion, we have shown that the adipogenic potential of n-6 PUFAs is modulated by cAMP signaling both in vivo and in vitro. Differences in culture conditions and feeding regimes affecting the glucagon/insulin ratio provide an explanation for the contradictory results published in the literature. Today's diets are abundant in n-6 fatty acids from vegetable oils (corn, sunflower, safflower, and soybeans) that are used in industrially prepared food. In addition, industrially produced animal feed is also rich in grains containing n-6 PUFAs, leading to meat enriched in n-6 PUFAs at the expense of n-3 fatty acids (39). n-6 PUFAs, predominantly linoleic acid, are now the predominant source of PUFAs in Western diets (23). PUFAs have been considered less harmful to human health than saturated fat, and substitution of saturated fat with PUFAs in general has been recommended by dieticians. If the background diet determines the adipogenic potential of n-6 PUFAs also in humans, this is of great concern, since the intake of refined sugars from sources such as soft drinks has increased dramatically during recent decades (40).
Background diet? Insulin-elevating carbohydrate. Result? Adiposity. Culprit? Linoleic acid.

I like this model because it provides a face-saving formula for many factions currently locked in bitter dispute, and because it seems to reflect the various realities we see around us. It's certainly not my job to help solve the obesity epidemic, but every now and then one can't help but take an interest, because the science gets good.
What will happen when fat, with normal protein, is substituted for carbohydrate? Less protein metabolism energy loss, different body composition, less COX-mediated prostaglandin but maybe the cAMP will still be elevated. On to the next experiment then.
Now about that proposed Kiwi saturated fat tax, supposed to increase our PUFA intake without decreasing our intake of carbs?
There's a thing called Unintended Consequences. I like this example, reminds me of the good old days:

Theobald Mathew's temperance campaign in 19th-century Ireland (in which thousands of people vowed never to drink alcohol again) led to the consumption of diethyl ether, an intoxicant much more dangerous due to its high flammability, by those seeking to become intoxicated without breaking the letter of their pledge.
(Ether in Ireland, from Psychology Today; Ether in Silesia, a fascinating J. Medical History article from PubMed)

The only thing that really worried me was the ether. There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge
- Hunter S. Thompson

(Music: Charlie Parker Live at Storyville, 1953)

Coeliac and non-coeliac gluten sensitivity, conditions which can cause (apart from the classic syndrome) cirrhosis of the liver independent of viruses or alcohol, are hard to treat by simple removal of gluten grains, because gliadin sensitivity creates cross-sensitivity to peptides found in other foods.
(Hat-tip to Suppversity for posting about this).

Gliadin (Wheat), Casein (Milk), Avedin (Barley and Oat) and Zein (Corn) peptides are prolamines (peptides with Pro-Pro bonds). But why does instant coffee feature at all? Well, coffee is a seed, but it doesn't appear to be a source of prolamines.
All of these cross-sensitivity prolamine allergens are also active at endorphin receptor sites; they are what is called exorphins. Wheat and milk can be addictive to persons who should be avoiding them, another reason coeliac is difficult to diagnose and treat. And roasted coffee beans also contain a compound which has endorphin receptor activity - except that it is an endorphin antagonist, and not a prolamine but a lactone formed from one of coffee's antioxidants.
There is no record of a link between coeliac disease and endorphins (at least, none that the cursory Google search that easily supplies all my other evidential links has uncovered), beyond the helpfulness of LDN (low dose Naltrexone) in CD recovery.
However, opioids (at least, the pharmaceutical ones) have two modes of action, one via the endorphin system, one via the immune system and TRL4 activity. Naltrexone is both an opioid antagonist and a TLR4 antagonist; and TLR4 is implicated in coeliac disease via non-gluten components of wheat, trypsin inhibitors.
(At about this point, the trail went cold. It would have been nice to link exorphins and TLR4, I had even dreamed about TLR4 antagonism and the benefits of coffee drinking, but it was not to be...)
Edit: here is a link between coffee and TLR4 inhibition, it's not about the exorphin, but there's hope for me yet.

Enlarged picture here

Coeliac and non-coeliac gluten sensitivity may be associated with Hepatitis C, and anecdotally a great many people with the virus find their health improves when avoiding the cross-reactive foods. Both coeliac disease (OR 3.1) and chronic HCV infection (OR 2-4) are associated with an increased rate of non-Hodgkin's lymphoma, and the autoimmune conditions commonly associated with coeliac are virtually identical to the extra-hepatic HCV syndrome. As an intracellular virus, HCV triggers the production of interferons, and interferon-alpha has a causitive role in coeliac. Coeliac disease has been triggered by INF-alpha treatment for HCV. However, gluten sensitivities are hard to diagnose and exist on a spectrum, with a significant proportion of people having some potential for sensitivity, and gluten sensitivity diseases may take time to develop. On average, cases of coeliac disease take 13 years to diagnose. This is plenty of time for someone to develop serious health problems or indeed die, without the involvement of gluten sensitivity being noticed.

(I have never been a fan of Interferon treatment for HCV; in my experience people who have avoided Interferon and treated themselves with diet and supplements tend to stay healthier overall than people who have done interferon but failed to respond to it. Indeed, I know people with chronic hepatitis C who stay healthy with no effort at self-treatment whatsoever. So far, the people I have known with HCV who have died of liver disease or needed transplants, other than alcoholics, are people who have taken Interferon but failed to clear the virus. People who do respond to Interferon can certainly improve, but this means that doctors prescribing Interferon need to be selective about who they offer it to. If it is prescribed to someone with no symptoms, or a low possibility of clearance, or a high risk of side effects on the basis that this is better than doing nothing, this is unlikely to be the case. Thankfully this question is becoming moot with the arrival of interferon-free treatments with a high rate of efficacy and minimal side-effects. Here is a grueling account of post-interferon problems.)

I think it entirely plausible that the post-treatment effects some people experience from Interferon therapy for HCV are mediated by the induction of sensitivity to wheat, milk, yeast, corn and other foods, and that the extra-hepatic and autoimmune syndromes of chronic hepatitis C have the same cause. This could include a wide variety of auto-immune conditions, not just gut disorders.
On the other hand, I am not in favour of eliminating so many foods from the diet that nutrition is compromised. Removing the main offenders - grains, legumes (also a source of trypsin inhibitors), yeast (bread and beer are the main sources of yeast), and milk (some dairy products low in casein, such as butter, may be OK), supplementing vitamin D and probiotics, and eating nutrient-dense foods mainly of animal origin for a while seems to be the best way to both heal the gut and reduce autoimmunity.

Another problem with grains, and with milk in people who are lactose intolerant, is SIBO, or an excess of bacteria in the small intestine. This is associated with progression of NASH and cirrhosis, and also with Vitamin B12 deficiency. It's a good fibre/bad fibre situation, with good fibres being those that ferment in the colon (large intestine).
Micheal Eades has just blogged about SIBO in the context of GERD, a common cause of eosophagitis (acid reflux, sore throat, difficulty swallowing, increased cancer risk).
Reading first the introduction to a vitamin primer, and then Protein Power, by Drs Michael and Mary Dan Eades first awakened me to the possibilities of low-carb, high fat diets for the treatment of inflammation and autoimmune disease. I'd like to thank the Drs Eades for writing books that became popular enough to become ubiquitous (and thus arrive at the Op Shops I get my books from) while remaining readable.
Here's one of my favourite NASH papers, just an abstract from a poster presentation at a conference - but how on earth does anyone get an omega 3:6 ratio of 1:144? Note that no-one here had 3:6 in or near the adaptive range of 1:1 - 1:5.

POLYUNSATURATED FATTY ACID COMPOSITION IN ERYTHROCYTE LIPID MEMBRANES IN NASH: UNEXPECTED HETEROGENEITY IN THE N6-N3 RATIO

S. Caldwell*, C. Argo, A. Al-Osaimi, N. Shah, H. Lothamer, C. Harmon, J. Rodriguez
University of Virginia, Charlottesville, VA, USA. *shc5c@virginia.edu

Introduction and aim: Essential dietary polyunsaturated fatty acids (PUFA) include omega-6 (n-6) linoleic acid (18:2) which is metabolized to arachidonic acid (AA) and omega-3 (n-3) linolenic acid (18:3) which is metabolized to eicosapentanoic acid (EPA). Imbalance in secondary eicosanoids and prostaglandin metabolites of n-6 and n-3 PUFA are implicated in disorders related to the metabolic syndrome. Skeletal muscle PUFA influences systemic insulin sensitivity (Borkman 1993) and diets rich in omega-3 fatty acids are associated with diminished histological injury in NASH (Musso 2003). Erythrocyte membrane lipids reflect dietary intake of essential fatty acid over preceding months. We measured erythrocyte n-6:n-3 ratio in a cohort of patients as part of a larger study of omega-3 fatty acid therapy of NASH.

Methods: 15 patients (10 female) underwent analysis of erythrocyte lipid composition using capillary gas chromatography (Metametrix, Duluth, GA) to determine the AA:EPA ratio. The mean age was 50 ± 13 years all with liver biopsy NAS score ≥ 5 and a range of non-cirrhotic fibrosis stages of stage 1 (n = 6), stage 2 (n = 5) and stage 3 (n = 4).

Results: The mean AA:EPA was 65 ± 34 reflecting a relative excess of n-6 PUFA overall. However, a broad range was noted from 15 to 144 AA:EPA. Dividing the group into quintiles of the reference range, 9 of the patients fell into the highest (5^th) quintile (AA:EPA = 84 ± 30) compared to the remaining 6 patients (AA:EPA = 36 ± 16, p = 0.001). There was no statistically significant difference in the histological stage between these groups (fibrosis score = 2 ± 0.9 versus 1.7 ± 0.8) although the higher AA:EPA group was significantly older (55±12 versus 39±12, p=0.01).

Conclusion: There is heterogeneity of AA:EPA in non-cirrhotic NASH patients and an age-related increase in n-6 to n-3 PUFA evident in the AA:EPA ratio of erythrocyte lipids. Further work is needed to understand if this reflects dietary differences and how this might influence response to omega-3 fatty acid therapy.

Here is a discussion of changing omega 3:6 in the US food supply: "The ratio of total n−6 to n−3 was 5.4 in 1909 and 9.6 in 1999". Average intake of omega 6 has always been sufficient but has become excessive, intake of omega 3 has always been inadequate.

This little paper should have made a minor splash in the paleosphere last week, but no-one really knew what to do with it.
It has 20 authors. Success has a thousand fathers, they say.

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

Abstract

Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.

The Polyol Pathway

To summarise - when extra glucose is consumed by mice, some of this is converted to sorbitol then to fructose. This is associated with elevation of AST and ALT. Mice that cannot convert convert glucose to sorbitol are protected from rises in fructose and liver enzymes. Therefore fructose is so bad for you that it even accounts for the metabolic harm of high glucose intakes.
"These studies show that glucose-mediated obesity, visceral fat accumulation, hyperinsulinaemia, hyperleptinaemia and fatty liver are all dependent in part on the conversion of glucose to fructose in the liver with the metabolism of fructose by KHK. In other words, the mechanism by which glucose induces its metabolic effects is largely dependent on fructose
metabolites resulting from the fructose generated from glucose by the polyol pathway".

But, one must insist - this is dietary glucose doing this, not dietary fructose. This is not evidence in support of the idea that fructose is the bad carb, and glucose is the good carb; it looks more like evidence that, in normal metabolisms, sugars are somewhat interchangeable.
If you consume an excess of glucose, hepatic metabolism will have to convert some of that excess to fatty acids. Palmitic acid will be synthesised, and some palmitic acid will be elongated to oleic acid (because you can't make a triglyceride with 3 SFAs - if there's no dietary MUFA, DNL oleate makes the process of esterification possible). But you'll also need glycerol, and fructose is said to be a better glycerol substrate than glucose (for some reason I don't understand, being hopeless at maths). Note the pyruvate as a source of fatty acids in the schema below - this could just as easily have come from glucose. Indeed, the acetyl-CoA to make fatty acids could have come from fatty acids. (This is what happens with linoleic acid in fatty liver disease. Indeed, this kind of futile cycling of lipid carbons seems to be a feature of NAFLD.)

In the context of hyperglycemia in the absence of dietary fructose, (one might speculate that) the generation of a little fructose makes sense, just as the elongation of palmitate to oleate makes sense, as a means of packing away energy from glucose into stable triglycerides (which can be exported from hepatocytes with VLDL, or stored more-or-less safely for a while) more easily than would otherwise be the case. Perhaps.

We fed the mice 10% glucose water and off they went.

The knock-out mice that couldn't change glucose into fructose consumed less glucose. The authors pulled out some KO mice (n=4) that ate as much as 4 non-KO mice, to show that the KO mice were healthier - fully protected against the metabolic harm of fructose/glucose - but this kind of post-hoc tactic is a bit suspect. Interestingly the KO mice had higher serum beta-hydroxybutyrate (ketone body) levels. I guess that energy had to go somewhere (is this at all relevant to the claims that potatoes elevate ketones?).

There are humans who cannot metabolise fructose or sorbitol.

"Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. Most adult patients do not have any dental caries".

Bill Lagakos says that his nutrition tutors spent all of five minutes on the polyol pathway; R.D. Feinman, who should know, states "I never saw the point or function of the polyol pathway".
Wild speculation aside, that's fair comment. The polyol pathway is useful for blinding diabetics, but it doesn't seem particularly essential for life. At most it might once have provided a slight buffer against hyperglycemia, but today we have far too many copies of the amylase gene and the polyol shock absorber, if that is what it was, is easily broken, making things worse. Is that any explanation? Some mysteries, it seems, are going to remain mysteries.

Fructose is a factor in fibrosis of chronic Hepatitis C: but it's not a biggie.

Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients.
Unhealthy food intake, specifically fructose, has been associated with metabolic alterations and with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of fructose intake with the severity of liver histology.

METHODS:

Anthropometric and metabolic factors, including waist circumference (WC), waist-to-hip ratio (WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy-proven G1 CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database. All biopsies were scored by an experienced pathologist for staging and grading (Scheuer classification), and graded for steatosis, which was considered moderate-severe if ⩾20%. Features of non-alcoholic steatohepatitis (NASH) in CHC were also assessed (Bedossa classification).

RESULTS:

Mean daily intake of total, industrial and fruit fructose was 18.0±8.7g, 6.0±4.7g, and 11.9±7.2g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR (p=0.02) and hypercaloric diet (p=0.001). CHC patients with severe liver fibrosis (⩾F3) reported a significantly higher intake of total (20.8±10.2 vs. 17.2±8.1g/day; p=0.04) and industrial fructose (7.8±6.0 vs. 5.5±4.2; p=0.01), not fruit fructose (12.9±8.0 vs. 11.6±7.0; p=0.34). Multivariate logistic regression analysis showed that older age (OR 1.048, 95% CI 1.004-1.094, p=0.03), severe necroinflammatory activity (OR 3.325, 95% CI 1.347-8.209, p=0.009), moderate-severe steatosis (OR 2.421, 95% CI 1.017-6.415, p=0.04), and industrial fructose intake (OR 1.147, 95% CI 1.047-1.257, p=0.003) were independently linked to severe fibrosis. No association was found between fructose intake and liver necroinflammatory activity, steatosis, and the features of NASH.

CONCLUSIONS:

The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1 CHC.

Excuse me, but OR 1.147 is not a huge correlation. It's as tiny as a red-meat-and-disease-of-your-choice correlation in a study run by vegans. What if they had looked at total carbohydrate? Or included fruit juice and high-GI glucose sources like bread and pasta? Do you think the OR would have been higher then? It was about OR 2.9for carbohydrate and fibrosis in the last Italian diet study I read.

Yes, my header does say limit fructose. And fructose might have special powers to harm, it's just hard to distinguish how strong those are when the trend is to put all the blame on them. The usual sources of fructose - sugar, HFCS, fruit juice - are mainly dumping carbohydrate directly into circulation, like that 10% glucose water the mice drank. They are high GI carbs. Or they would be if F was also G. But F is also G, and G is also F.
If we can learn anything from the polyol pathway, it is, that carbs will be carbs.

P.S. remember from the NASH posts how taurine is good for removing excess cholesterol from the liver? And generally hepatoprotective?

Sorbitol accumulation depletes taurine:
Prevention of sorbitol accumulation with the aldose reductase inhibitor sorbinil increased nerve taurine levels by 22% (p < 0.05) when compared with untreated diabetic animals. Thus, we have demonstrated an interdependence of organic osmolytes within the nerve. Abnormal accumulation of one osmolyte results in reciprocal depletion of others. Diabetic neuropathy may be an example of maladaptive osmoregulation, nerve damage and instability being aggravated by taurine depletion.

This blog exists to promote the hypothesis that carbohydrate restriction (plus the restriction of the omega 6 PUFA linoleic acid) is an effective antiviral strategy against Hepatitis C virus. Or conversely, that dietary carbohydrate and linoleic acid are HCV growth promoters. (Of course this blog also exists for my entertainment, self-aggrandizement and so on, but clearly if my hypothesis fails I will have to find another title for it). Thus far the hypothesis has rested on the emerging facts about HCV genomics and life history and a second-hand copy of Dr Atkins New Diet Revolution, with some vague support from the epidemiological research into Hep C and diet (so far, a collection of such arbitrarily heterogenous methodologies as to bury the very possibility of any future meta-analysis) and the old n=1.
No study existed that could honestly be seen as testing the HCV-carbohydrate hypothesis at any level. Or so I thought; but thanks to informants Silvia and Samir, I received this 2011 paper yesterday

Microbiol Immunol. 2011 Nov;55(11):774-82. doi: 10.1111/j.1348-0421.2011.00382.x.

Inhibition of hepatitis C virus replication through adenosine monophosphate-activated protein kinase-dependent and -independent pathways.

Nakashima K, Takeuchi K, Chihara K, Hotta H, Sada K.

Source

Division of Microbiology, Department of Pathological Sciences, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, Kobe, Japan.

Abstract

Persistent infection with hepatitis C virus (HCV) is closely correlated with type 2 diabetes. In this study, replication of HCV at different glucose concentrations was investigated by using J6/JFH1-derived cell-adapted HCV in Huh-7.5 cells and the mechanism of regulation of HCV replication by AMP-activated protein kinase (AMPK) as an energy sensor of the cell analyzed. Reducing the glucose concentration in the cell culture medium from 4.5 to 1.0 g/L resulted in suppression of HCV replication, along with activation of AMPK. Whereas treatment of cells with AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) suppressed HCV replication, compound C, a specific AMPK inhibitor, prevented AICAR's effect, suggesting that AICAR suppresses the replication of HCV by activating AMPK in Huh-7.5 cells. In contrast, compound C induced further suppression of HCV replication when the cells were cultured in low glucose concentrations or with metformin. These results suggest that low glucose concentrations and metformin have anti-HCV effects independently of AMPK activation.

1 g/L glucose is 5.5mM with the normal physiological range for fasting BG being 4-7 mM. ("The fasting value is within the range of 4-7 mM, with minimum individual variance from day to day, despite varying life conditions with food and exercise.")

The effects are explicable in terms of glucose+insulin upregulating DGAT1 (required for viral completion) and downregulating PPAR-alpha (hepatic fat-burning transcription factor and implacable enemy of HCV replication).

Now there is a common objection to any method of inhibiting viral replication, that viral load does not always correlate with liver damage in Hepatitis C (though it does influence the response to treatment). There are three main reasons why this is so;

- Taking a viral load PCR and simultaneous fibroscan does not tell you how long someone has been infected, and duration of exposure will eventually become a more important factor than quantity of virus.

- There are other factors that determine liver inflammation independently of HCV, for example alcohol, or the omega 6 & carbohydrate combo that produces NAFLD.

- And – the relevant point here – a low viral load might indicate a low rate of replication, but could also indicate a relatively high rate of replication, but with a more active immune response both suppressing the virus and contributing to liver damage. In which case, the lower the rate of replication, the less damage will be done, both by the virus and its toxic proteins, and by the immune complexes, Il-17 T helpers, and other aspects of a chronically activated immune system trying to deal with it.

The mysterious "Compound C", an AMPK inhibitor

The mysterious “Compound C” which inhibits AMPK is interesting too. AMPK is basically controlling your cell’s metabolic rate. At higher glucose levels, more AMPK = less HCV replication. But at the lowest glucose level, where HCV replication is inhibited, lowering AMPK with Compound C inhibits replication even further. rT3 anyone?

Anyway, there is no point having low fasting blood glucose if you are not usually fasting, so any attempt to exploit this effect by a low-carb diet (and I don’t rule out other types of diet also being able to keep fasting BG around 1 g/L or 5.5mM for some people, but VLCKDs do seem the obvious choice) should probably be in an intermittent fasting context like 16:8. Also, the point might not be to obsessively measure blood glucose and keep it at 4mM, but simply, if it’s high, try to get it a bit lower; within the normal range of 4-7mM being better than above it. 4.5 g/L was chosen in the study as an abnormally high blood glucose level, one associated with type 2 diabetes, a disease associated with chronic HCV infection.
(note: I appreciate that in the US, Egypt, and some other countries BG is measured in mg/dL, which is 100x the g/L measurement, and that there is probably a great deal to be said about what range is ideal, so I have just stuck to received opinions and kept the scienticians' g/L counts, as I am a novice to the business of measuring BG. The only fasting BG test I could could find of my own was 6mM, on a moderately low carb diet (100-150g); it isn't something my doctors usually order.)

The Kinks found that low-carb diets were perfectly effective for weightloss in 1970

(Update 1 - in HCV Gt2-infected Huh 7.5 cells, glycolysis is upregulated, as is lipogenesis and gluconeogenesis, while glucose uptake is down regulated. "Although infected cells may be attempting to counter the HCV-induced low cellular glucose levels by increasing gluconeogenesis, they appear to be unable to counteract both increased glycolysis as well as decreased glucose transport". This might be what makes HCV assembly especially vulnerable to low ambient glucose levels.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427885/

Update 2 - Many of the lipid metabolism genes upregulated in this study are targets of the PPARα transcription factor (40). One of these genes, the TXNIP gene, which functions as a negative feedback inhibitor of PPARα (33), was shown to be essential for HCV replication and secretion by siRNA silencing. A recent study demonstrating that agonists of PPARα suppress the replication of HCV indicated that the inhibition of PPARα by TXNIP may be important for HCV infection (32). Increased expression of TXNIP also occurs when intracellular glucose levels are high (14). A recent siRNA screen for host factors involved in JFH-1 HCV replication demonstrated that silencing MXLIPL, a glucose-responsive transcription factor that induces TXNIP expression, also significantly reduced JFH-1 replication.
http://jvi.asm.org/content/84/10/5404.full

In addition, hepatic overexpression of a Txnip transgene in wild-type mice resulted in elevated serum glucose levels and decreased ketone levels.)

The Credit-where-it's-due department thanks Carbsane for posting about this paper, which indicates that HbA1c may not be a reliable measurement of long-term glucose levels in people with chronic Hep C, who may have deficient or short-lived hemoglobin, and therfore artificially low HbA1c levels for this reason.
"In the present study, participants with low HbA1c values had unfavorable profiles of red blood cell related factors, iron storage, and liver function."

In ancient times, those suffering from ye surfeit of choleric humours were prescribed a purgative compounded of tincture of statin. Modern science, from its evidence-based wisdom, has compounded a new elixir by the name of Alirocumab (the drug being named after its father, one of the Legions of Satan listed in the Enochian Book of Revelation).

Music: Rasputina, "The Signs of the Zodiac"
Do you believe in the Signs of the Zodiac?
Haven't you found that the systems for
Planning always fail?

Can you avoid what gave Daddy his heart attack?
Have you tried everything, anything
All to no avail?

I know what you need.
This will really work.
In ancient times, if you were sick
They make you bleed.
Oh, honey I know it hurts.

Alirocumab has the remarkable property of reducing cholesterol by 47.2%. At this rate cholesterol will soon be as rare as smallpox. Alirocumab is a fortnightly-injectible antibody that inhibits a protein called PCSK9, which regulates hepatic lipoprotein uptake by degrading LDL receptors and preventing them from being re-used. Less PCSK9, more LDL receptors, more cholesterol, lipids etc. going into hepatocytes. What could possibly go wrong?

Human PCSK9 is known to enhance the degradation of membrane-bound receptors such as the hepatocyte low-density lipoprotein receptor (LDLR), ApoER2, and very low-density lipoprotein receptor. Because the LDLR is suspected to be involved in hepatitis C virus (HCV) entry, we also tested whether PCSK9 can affect the levels of CD81, a major HCV receptor. Interestingly, stable expression of PCSK9 or a more active membrane-bound form of the protein (PCSK9-ACE2) resulted in a marked reduction in CD81 and LDLR expression. Therefore, we analyzed the antiviral effect of PCSK9 in vitro using the HCV genotype 2a (JFH1) virus. The results clearly demonstrated that cells expressing PCSK9 or PCSK9-ACE2, but not the ACE2 control protein, were resistant to HCV infection. Furthermore, addition of purified soluble PCSK9 to cell culture supernatant impeded HCV infection in a dose-dependent manner. As expected, HuH7 cells expressing PCSK9-ACE2 were also resistant to infection by HCV pseudoparticles. In addition, we showed that CD81 cell surface expression is modulated by PCSK9 in an LDLR-independent manner. Finally, in the liver of single Pcsk9 and double (Pcsk9 + Ldlr) knockout mice, both LDLR and/or CD81 protein expression levels were significantly reduced, but not those of transferrin and scavenger receptor class B type 1. Conclusion: Our results demonstrate an antiviral effect of the circulating liver PCSK9 on HCV in cells and show that PCSK9 down-regulates the level of mouse liver CD81 expression in vivo. Therefore, we propose that the plasma level and/or activity of PCSK9 may modulate HCV infectivity in humans. (Hepatology 2009.)

So lowering cholesterol with Alirocumab looks set to increase the spread of hepatitis C. But what else decreases PCSK9? If PCSK9 increases LDL (the "bad" cholesterol), does saturated fat increase PCSK9?
The answers may surprise you.

Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.
We previously showed that hepatic PCSK9 expression is subjected to nutritional regulation, being decreased upon fasting and increased following re-feeding with a high carbohydrate diet in rodents[14]. Insulin increases hepatic PCSK9 expression both in vitro in hepatocytes and in vivo in mice[14]. Conversely, PCSK9 is repressed by glucagon in rat liver [16]. Accordingly, fasting, but not a ketogenic diet, reduces plasma PCSK9 concentrations in healthy volunteers, with a ≈ 20–35% decrease after 18 h [17,18]. However, so far there are only two reports that describe a dietary modulation of PCSK9 in human. The Mediterranean diet [19] and n-6 PUFAs [20] have been shown to decrease plasma PCSK9 concentrations by ≈ 12% and 13%, respectively.

And again:

PCSK9 (P = 0.001), TNF receptor-2 (P < 0.01), and IL-1 receptor antagonist (P = 0.02) concentrations were lower during the PUFA diet, whereas insulin (P = 0.06) tended to be higher during the SFA diet. In compliant subjects (defined as change in serum linoleic acid), insulin, total/HDL-cholesterol ratio, LDL cholesterol, and triglycerides were lower during the PUFA diet than during the SFA diet (P < 0.05).
(Note that this was not a high-fat diet "The participants were instructed (unblinded) to change the quality of their dietary fat without altering their intakes of total fat and the type and amount of carbohydrates and protein. The participants were encouraged not to change their physical activity or their fish and alcohol intakes during the study. Some key food items were provided: the PUFA group received foods rich in n−6 linoleic acid, ie, scones (baked-on sunflower oil), margarine, sunflower oil, and sunflower seeds, and the SFA group received scones (baked-on butter) and butter.")

Taking this all together - rather messy and unsatisfactory though it may be - it appears that saturated fat does not significantly increase PCSK9 levels, nor does protein (insulin and glucagon in balance), but that high fructose/carbohydrate and insulin do. High linoleic acid decreases PCSK9.

Now, however desirable elevated PCSK9 may be to people with HCV, we don't want to achieve it with elevated carbohydrate and insulin because this will switch off PPAR-alpha, the other antiviral protein.

The PPAR-alpha transcriptome in a human hepatocyte

Your classic LCHF Paleo diet is designed to maximise PPAR-alpha while leaving PCSK9 intact.
And that surfeit of choleric humours? It looks very much like the fructose, carbohydrate and insulin axis was responsible for any PCSK9 contribution to that.
Will people henceforth be dosing with Aloricumab so that they can enjoy sweet and starchy treats without alarming the doctors who audit their lipid returns?
This is the world we live in.

Anyway here is The Strangest Book in the World, accompanied by some rather wonderful music

And Part 2:

Leaky gut, AKA intestinal permeability, is one of the determining factors in diseases of the liver, which should be tolerant of the normal adaptive quantities of lipopolysaccharides (LPS, fragments of Gram-negative bacterial cell walls) that reach it (other parts of the immune system need to be more sensitive to LPS). If too much LPS reaches the liver because the gut barrier is weakened, or if the liver is made over-sensitive to LPS by factors such as steatosis and cholesterol accumulation, LPS activation of TLR4 can set in motion the immune cascades that lead to fibrosis and necrosis.

TLRs are sensors that amongst other things help orchestrate responses to both potential pathogens and symbiotic organisms. Having just had to replace one of the many sensors in my car that keeps the engine in tune and alerts me to problems, I'm thinking that might be an acceptable analogy for now. A defective sensor crippling the engine to alert me to a problem that doesn't exist is a bit like an allergic reaction, maybe.
Gut integrity is modulated by TLR2

Our findings suggest that dietary saturated fat plays a protective role against MCDD-induced steatohepatitis, whereas TLR-2 deficiency exacerbated NASH. The mechanism underlying the response to dietary fat and TLR-2 likely involves altered signalling via the TLR-4 pathway.

TLR2 is activated by saturated fat, inhibited by polyunsaturated fat.
Dietary saturated fat protects against LPS (endotoxin) activation of TLR4 in hepatic immune cells, but different SFAs achieve this in different ways.

2013 Oct 10. [Epub ahead of print]

Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats.

Zhong W, Li Q, Xie G, Sun X, Tan X, Sun X, Jia W, Zhou Z.

Source

1University of North Carolina at Greensboro.

Abstract

Endotoxemia is a causal factor in the development of alcoholic liver injury. The present study aimed at determining the interactions of ethanol with different fat sources at the gut-liver axis. Male Sprague Dawley rats were pair-fed control or ethanol liquid diets for 8 weeks. The liquid diets were based on the Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long chain saturated fatty acids) or medium chain triglycerides (MCT, exclusively medium chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration, and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanol-induced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and ZO-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of the endotoxin detoxifying enzymes argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent.

Meaning: Coconut oil MCTs (also found in butter/ghee and palm oil) normalised serum LPS level by repairing gut integrity, whereas cocoa butter protected the liver by enhancing the clearance or detoxification of LPS.

Spirulina is a TLR2 agonist and protects against inflammation in chronic hepatitis C. Probiotic (Gram-positive) bacteria also protect the intestinal epithelium via TLR2;

All the Gram(+) strains increased the number of TLR-2+ cells and the Gram(−) strains [increased the number] of the TLR-4+ cells.

VSL#3 is a popular probiotic mix approved for medical use in Europe ("VSL#3 is a probiotic mixture which has been frequently referred to in the literature, and contains live lyophilized Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus and Streptococcus thermophilus.").

Here is a very interesting new paper which compares, in a alcohol model of liver/gut disease, combinations of live VSL#3, heat-killed VSL#3, and l-glutamine (amino acid fuel preferred by enterocytes and protective thereof).

Results

First, compared with control group, endotoxin and TNFalpha in alcohol group was obviously high. At the same time, in VSL#3 group, the expression of endotoxin and TNFalpha obviously lower than the alcohol group. And the trends of the expression of tight junction proteins in these groups were reversed with the change of endotoxin and TNFalpha. Second, compared the groups of VSL#3 with glutamine, VSL#3+glutamine and heat-killed VSL#3, we found that both VSL#3 and heat-killed VSL#3+glutamine were as effective as VSL#3+glutamine in the treatment of acute alcohol liver disease, the expression of endotoxin and TNFalpha were lower than the alcohol group, and tight junction proteins were higher than the alcohol group whereas the expression of tight junction proteins were higher in VSL#3 + glutamine group than either agent alone, but have no significant difference.

Did you get that? The full text is a little different:

We found that both VSL#3 and heat-killed VSL#3 were as effective as

glutamine in the treatment of acute alcohol liver disease, whereas the combination of VSL#3

and glutamine therapy efficacy was more effective than either agent alone

So maybe - and this is backed up by other research - for some purposes the viability or resistance or age or condition of a probiotic supplement can be less important than the strains and number of organisms it contains. And yoghurt cooked into meals, which appears to be a common thing in countries where yogurt is a traditional food, with only Western faddists consistently fetishizing rawness, might have its medicinal uses too.

Lamb baked in yogurt

Certainly, a probiotic need not make it alive all the way through the digestive tract to influence host immunity, and some of the objections commonly made in "evidence based" criticisms of probiotics are simply not relevant to some important probiotic modes of action.

"The probiotic paradox is that both live and dead cells in probiotic products can generate beneficial biological responses. The action of probiotics could be a dual one. Live probiotic cells influence both the gastrointestinal microflora and the immune response whilst the components of dead cells exert an anti-inflammatory response in the gastrointestinal tract."

So here we have a mixture of strategies to combine to repair a leaky gut and reduce consequent hepatic inflammation;
1) dietary saturated fats of both MCT and long-chain classes
2) l-glutamine
3) spirulina
4) viable live probiotic cultures (and prebiotic fibres)
5) killed probiotics, as well as live commensal species that do not easily colonise the gut

"FOOD GROUP TO SPLIT - IRRECONCILABLE DIFFERENCES CITED" is a headline I expect to see any day now. The notion of the Food Group seems to have become the most abused concept in Nutrition. Two recent examples are the criticism of Paleo - "Excluding grains means leaving out an entire food group, that can't be healthy"; and the following mention in an otherwise laudable piece by Lucy Cavendish in support of Dr Aseem Malhotra's BMJ article in defense of saturated fat (I'm sure I don't need to link to that).
"With wheat and gluten vilified in recent years, I have, in the past, cut both food groups from our household diet – and it has cost me a small fortune."

Let's charitably assume that "gluten" in that sentence refers to the other gluten grains, or to non-grain products with a "contains gluten" warning on the box, and not to the protein itself. It's still wrong, if the Food Group concept is to mean anything. And if grains can be a food group, why not eggs? Wheat grains, barley grains, rye grains, rice grains; hen eggs, duck eggs, quail eggs, goose eggs. If we did this, how many food groups would there be?
Why do we have a concept of Food Groups in the first place? And what would be the most rational and useful system to use today, if any?

According to the NZ Nutrition Foundation website, Using food groups is a way of classifying foods according to the nutrients they provide. Here in New Zealand, the four food groups are:

Fruit and Vegetables
Breads and cereals (bread, rice, pasta, breakfast cereals)
Milk and milk products (milk, cheese, yoghurt, ice cream)
Lean meat and alternatives (lean meat, poultry, seafood, eggs, nuts & seeds, beans and lentils)

Or, indeed, according to the nutrients they don't provide - lean meat isn't a food group, but the indication of an eating disordered way of thinking here. This is taken to a further extreme in the latest Health2000 newsletter, where there are "5 main food groups" (ignoring how many subsidiaries?)

Fruit and vegetables
Whole grain breads and cereals (bread, rice, pasta, oats)
Lean protein foods or vegetarian alternatives (egg, fish, lean meat, poultry, legumes, nuts)
Dairy products (milk, yoghurt, cheese - preferably low fat)
Small amounts of healthy fats (olive oil, nuts, seeds, avocado)

Which fiendishly refines the 4-group scheme by removing a nutrient from two of the four groups, then introducing an additional group to supply it.
It is a relief to leave such complexities behind to return to a simpler time, when the goal of nutritional teaching was to ensure that people knew enough to be adequately fed and raise healthy children (a need that persists today, but you wouldn't know it). In 1936 there were three food groups -

Body Building Foods (those foods that are high in protein, but not necessarily lean)

Protective Foods (those foods that are good sources of vitamins, especially vitamins A, D, C, and folate)

Energy Foods (Fat, sugar, and starch; the more-or-less empty "discretionary calories")

These 3 food groups are introduced at 4:00 in this short film

Now you may laugh at the idea of treating carbohydrate and fat as interchangeable, but compared to the byzantine dietary adjustments we've been discussing, and considering that the Body-building and Protective groups here already supply a generous fat intake by modern standards, it seems eminently sane to me.

This Disney educational cartoon from 1955 (made for a South and Central American audience under the Good Neighbour policy of the Cold War years it seems) takes a similar approach, except that the Energy Foods are now Grains and Roots, and the other 2 groups are Animal Foods, and Vegetables and Fruits (the latter group "builds strong bones and teeth").

Our third example is from 1967 and is interesting as a treatment of obesity at a time when this problem was rare, and because macronutrients and micronutrients are introduced (3:25). Food supplies Protein, Carbohydrate (for energy), Fat (for warmth and energy), and "those vitamins we hear so much about today".

(In part 3 of this film the doctor will tell the kid to cut down on starchy and sweet food, and to eat meat and veges. No mention of lean meat or low-fat dairy. No doubt one reason obesity was still rare in 1967)

I don't know about you but I prefer these simpler approaches. I like the idea of having four groups (remember, this is really for teaching children, and people who've never thought about nutrition much, not something adults will need to remember).

Body building foods, i.e. protein sources. Animal foods, and maybe nuts and seeds, but unless you're avoiding meat for some reason, legumes are probably better in the next section. If you don't tolerate dairy, don't eat it.
Starchy foods; roots, bananas, grains, legumes and so on. If you don't thrive on gluten grains, don't eat them. Also honey, molasses and treacle. Cooked fruits.
Fatty foods; butter, dripping, oils, cod liver oil, cream, coconut, avocado, etc. Nuts and seeds here too? In the tradition of the 1936 and 1967 films, a great deal of overlap is simply realistic and consistent with the facts (Myplate as a Venn diagram?).
Vegetables and fruits, i.e. foods that don't supply much in the way of energy or protein but do supply vitamins, antioxidants, fibre, electrolytes and other protective factors. Herbs and spices can go here too.

This list isn't satisfying. It's judgmental, for one thing; what does one do with sugar? Fruit juice? "Treats" (odious word) and "snacks" are not food groups but social problems. As for honey, that's an animal food, isn't it? And what about alcohol, the rogue macronutrient? Where does chocolate go? What about this crazy new trend of calling water a food group?
How much propagandizing is permissible? I'd be tempted to say "as much as is necessary", but only if you can sell it in the face of questions. It would be better to include sugar in the list than to lack a good explanation for leaving it off. And so on. The virtue of a list like this is that it introduces the macronutrients and protective factors using real examples.

The rest is cookery.

Question:
I'd like to read your own suggestions for a reformed Food Group system, or, failing that, see your favourite egregious examples of depraved Food Group systems from the current culture.

Dr Richard Mackarness

In Chapter 7 of his influential 1970's book on food allergies "Not All In The Mind" U.K. physician Dr Richard Mackarness describes his encounters with the pioneers of low-carb medicine when he visited the States in 1958. That same year Dr Mackarness wrote "Eat Fat and Grow Slim".
"His first book, Eat Fat and Grow Slim (1958), exposed the "calorie fallacy" and proposed a non-carbohydrate "Stone Age" diet of protein and fat with no restriction as to the amount eaten. The book was immensely popular and went through six editions."

$T2eC16Z,!ysE9sy0i2WDBRCevDN7Eg~~60_35

In the US Dr Mackarness interviewed, or studied the works of, the following "anti-cereal" doctors. Those that are covered in "Good Calories/ Bad Calories" or well-referenced on the internet I will treat briefly, I am mainly interested in drawing attention to some unsung heroes and their tales.

Dr Ray Lawson was a surgeon at one of the biggest hospitals in Montreal and surgical consultant to the Canadian Arctic Medical Service. Some of his Eskimo patients in the far north were still eating their old high-fat, high-protein, non-cereal diet, which seemed to him to keep them remarkably fit and give them great powers of endurance. He decided to try to lose some unnecessary weight by following an Eskimo diet himself, an enterprise in which he was completely succesful. just before I visited him, he had confounded his personal physician by curing himself of an attack of jaundice. His doctor had been treating him with orthodox methods, including a low-fat diet, without much success.Dr Lawson switched to large doses of double cream, and promptly got well. An article about him and his high-fat eating was published in the popular Canadian magazine Maclean's, and caused quite a stir.

After seeing Dr Lawson I visited the late Dr Alfred Pennington of New Jersey who was consultant physician to Du Pont, the vast chemical company...he was asked to develop a reducing plan for the company's overweight executives... most of them had high blood pressure and were potential stroke- and heart-attack victims.
The diet he prescribed completely eliminated foods of cereal origin, i.e. everything containing starches or sugars; it was virtually an all-meat diet with the fat left in. When I lunched with him at his house I found he practised what he preached; we had an all-meat meal. He told me that he gave the duPont executives about 3000 calories per day in the formof fat meat and on this regime they lost at the rate of two to three pounds per week. They liked the diet, nd by the time their weight had returned to normal, their blood pressure had returned to normal too.
The relationship between obesity and high blood pressure is recognised by doctors all over the world, and the type of high blood pressure known as 'idiopathic' (of unknown cause) is one of the commonest stress disorders of twentieth-century civilised countries, crippling millions every year. It is a forerunner of strokes and coronary thrombosis. I believe that it and its associated obesity are both diseases of maladaptation to certain foods and chemicals we have been eating in increasing quantities over the past sixty to seventy years.

From Pennington I went on to Minneapolis to talk to Dr. George L. Thorpe, a general practitioner from Wichita in Kansas, who was attending the 1958 annual meeting of the American Medical Association. At the previous annual general meeting in New York in 1957, Thorpe had been chairman of the section of General Practice and had made the cereal-elimination approach to overweight the subject of his address .
Thorpe told me that he hated to call his method a diet. "Proper eating is the normal and complete answer to the problem of excess weight," he said. "The words diet and dieting should be avoided.

"Several years ago," Thorpe went on, "while I was considering a personal problem of excess weight, it became evident that huge numbers of calories in my daily total came from three to four large glasses of milk, two to three bottles of soft drinks, numerous slices of bread, and an educated taste for cookies, candy and sweets in general, all of which are concentrated carbohydrates. Cereal grains, historically, were cultivated in order that limited agricultural areas might supply food to support population densities not otherwise possible. They are concentrated forms of food, readily assimilated in the body, containing small residue of bulk, and so may be eaten in quantities far in excess.of the calorie needs, without sensation of fullness. All carbohydrate foods and most drinks fall into this category, either by virtue of their origin or the reaction of the body to them. Milk is actually a liquid infantile food, the use of which man has carried over into his adult life and which, in general, satisfies the definition of concentrated carbohydrate.
"The simplest to prepare and most easily obtainable high-protein, high-fat, low-carbohydrate diet and the one that will produce the most rapid loss of weight without hunger, weakness, lethargy or constipation is made up of meat, fat, and water. The total quantity eaten is not important, but the ratio of three parts lean to one part fat must be maintained, as any decrease in the fat portion will reduce the weight loss..
"Black coffee, clear tea and water are used without restriction. reduction of salt, while not required, will increase the speed of weight loss"

The last doctor I met was the late Blake Donaldson (he died in 1963). When I saw him at his clinic in New York I found that not only was he slimming his fat patients on a cereal-elimination diet, but he was using this diet and a graduated system of simple exercises to clear up a whole variety of chronic disorders in a most remarkable manner. I saw elderly rheumatic patients made supple and pain-free, martyrs to migraine relieved of their headaches and asthmatics helped to breathe freely again. In an interview in 1962, when he came to London to visit a patient Donaldson told me how he did it.

Dr MACKARNESS: When and how did you first come on the ideas which caused you to write Strong Medicine?

Dr DONALDSON: About 1919. I was faced with the problem of people with heart disease, fat people who were short of breath, had swollen feet (oedema) and could not lose weight. I tried them for a year on a low-calorie diet with a very bad result. At the end of the year practically none had lost weight, they were still breathless and had not lost their oedema.

[I wish I could copy all of this interview but it is far too long for my single-fingered typing skills. Dr Donaldson followed an investigative route similar to that of Weston A Price, except he looked at teeth in museum specimens. I think those heads have since had to be returned. The story is told in Strong Medicine beginning on page 32. Dr Donaldson talks of an "allergy" to flour, which is a terminology and concept Dr Mackarness later adopted. Its use means that the response to these foods is maladaptive and stressful, without always implying an immunological basis for this, which the scientists of the day were in no position to determine with certainty.]

Dr DONALDSON: We found out the patients could live on just fresh meat and a cup of coffee three times a day, and lose weight at the rate of three pounds a month. (You don't want to lose weight much faster than that, otherwise the skin becomes wrinkled.)
...
When you reduce their weight to normal you have to prove their weight can stay normal; that's very important...They have to be able to eat fat meat with salt, potato with butter, raw fruit and a full cup of coffee three times a day and show no gain in weight...there is no restriction on the amount.

Dr MACKARNESS: How many patients over the last forty years have you treated on this basis?

Dr DONALDSON: About seventeen thousand. I now have a group of about fifteen hundred patients over the age of seventy, who have avoided flour for between five and forty years,.and have kept primitive food as their basic way of maintaining health.

Dr MACKARNESS: This is what I call a Stone-Age diet. Would you agree with that description? It is a pre-cereal diet.

Dr DONALDSON: Well, I should say that it is perhaps six thousand years old and twenty years ahead of its time. I think this will be a popular idea in twenty years, that flour is a bad thing for about eighty percent of the population.

Dr MACKARNESS: And do you also ban all carbohydrate derivatives - sugar, chocolate, etc?

Dr DONALDSON: Once you have an allergic fat person under control you reduce that person's weight to normal. I find that I am unable to feed them sugar in any form, and unable to feed them flour, without bringing back their obesity and their allergic symptoms.

Dr Mackarness goes on to discuss F. Curtis Dohan and his 1969 work on schizophrenia and coeliac disease. He then describes the work of Andresen (1942) that ulcerative colitis is a result of food allergy "in 66% of cases" and that of Professor S. C. Truelove of Oxford who wrote in 1961 about improvement of ulcerative colitis upon removal of milk from the diet. These are both early descriptions of a disease due to lactose (or FODMAP) intolerance.

Mackarness returned to the UK and wrote the highly successful diet book Eat Fat To Grow Slim. Dr John Yudkin, a far more conservative academic nutritionist, also wrote a low-carb book, This Slimming Business, with similar recommendations to those of Mackarness, as can be seen in this 1970 paper. I wish I knew something about the relationship between these two great men. It cannot have been an easy one, as Yudkin was a cautious sceptic and Mackarness a speculative innovator. Mackarness bears responsibility for the popularising of elimination diets; these were harmless when meat was the default food, as it was in Not All In The Mind, but are more problematic now that the idea has been adopted by Naturopaths with eating disorders and strange ideas about animal foods.

The biggest difference between the British and American low carb doctors is, that Yudkin and Mackarness were respected members of the British medical establishment, and their ideas were given common currency by a country with a then-progressive approach to preventive medicine. You can see it in this 1967 video, where an overweight child is told to eat meat and green vegetables, and avoid sweet and starchy foods. Stodge, not grease, was the enemy and the cause of Overweight and Shortness of Breath.

Regardless of whether the consumption of starch and sugar has changed during the obesity epidemic, we can be quite sure that the advice given to the most vulnerable people - the newly overweight or pre-diabetic - has. In my opinion this is what we should be looking at - whether alterations in the primary diet and exercise advice given to individuals in at-risk groups by the most authoritative agencies has been associated with any particular outcome.
But really, I think we all know the answer to that.

This study on supplement use hasn't come up on the paleo radar, but it's a good example of how to expose junk epidemiology. It's from the Orthomolecular Medicine News Service - you can subscribe here and it's well worth doing, they don't mail often and are in the process of becoming accepting of low-carb science (such as ketogenic diets for cancer) while trying to cling to the saturated fat is bad, only vegetables and supplements are healthy message. Because these are not stupid people, and they already have methods that work, it's an interesting struggle to follow. Their archives link is here.
It's another junk study from Sweden - what is it about those Swedes? Is it a case of scientific suevism?
I love that he refers to Bayesian analysis as the way to proceed in these cases. I'm no mathematician, but it makes sense to me.

At the foot of the page I've included an abstract from a review of vitamin C for prevention of Complex Regional Pain Syndrome. This is an impressive result; 0.22 relative risk of this debilitating after-effect of fracture surgery from supplementing 500mg or more ascorbic acid daily for 45-50 days. An unusually effective clinical use for any supplement.
While the authors of the various trials cite the antioxidant effect of ascorbic acid and the toxicity of ROS as a mechanism, I suspect that improved integrity of the collagen matrix in the early stages of bone regrowth might also account for these benefits. After all, that's why ascorbic acid is a vitamin.

Music; Intermezzo from Cavalleria Rusticana by Pietro Mascagni.

Cataracts and Vitamins: The Real Story

by Damien Downing, MBBS, MSB, and Robert G. Smith, PhD

(OMNS Mar 5, 2013) "Hidden danger of everyday supplements is revealed" blared the headline in the UK Daily Mail [1] - a newspaper that is well known for declaring that, for example, "coffee causes cancer" and "coffee reduces cancer risk" on different pages of the same issue. This time it is reporting on a study out of Sweden that appears to show that taking vitamin C or vitamin E supplements increases your risk of developing a cataract - by about 20% for C and 60% for E. [2] It makes a good headline, but does it make sense?

Is this research?

No. They didn't give anybody anything, or do anything to them, This was just a computer exercise in which they re-analyzed postal questionnaires sent to the entire male population aged between 45 and 79 in an area of Sweden, and matched the responses to another database of cataract operations. Although the title says that it is "a population-based prospective cohort study," prospective would really mean that they followed the group of subjects, the cohort, closely over a period of time, without losing many of them. In fact they simply had their computer go through some old electronic records. Nobody was interviewed, and no checks or validation exercises were carried out. No researcher met any of the men in the study, ever.

Is it reliable?

No. The first really serious shortcoming of this paper, the gorilla in the room, is that half the men never replied in the first place, and then the authors deliberately excluded a lot more for reasons such as diabetes - one of the other main "outcomes" of the study and a big risk factor for cataracts. Finally, they omitted to account for another few thousand people, so that in the end they were only studying 27 percent of the original population. If they had randomly selected this sample of the population that would be fine, but in fact the subjects selected themselves by bothering to fill in and return the questionnaire, or not. What were their reasons? We know not. That means that already several types of selection bias have been introduced, and all the results are now meaningless.

There could even be what's known as indication bias - when cause and effect get mixed up. So, for instance, cataracts can take decades rather than years to develop, and people with early symptoms might be more likely to take supplements to ease their eyestrain. If the study goes on entirely in a computer, there's no way of telling.

Is it scientifically plausible?

No. The study contradicts many other studies that have shown either no effect or actual benefits of vitamin C and E for preventing cataracts and other eye diseases. Cataracts are common among older people, and it is well known that antioxidants can reduce the risk of developing them if taken long-term. Smoking, obesity, and diabetes are well-known risk factors for cataracts, and antioxidants are known to prevent the damage caused by these factors. [References below]. In one study, vitamin C supplements taken over 10 years or more reduced the risk of cataracts by about 80%.This is a huge dose-related effect, strongly suggesting the benefit of antioxidants in preventing cataracts. The effect was not apparent for short-term use, suggesting that any shorter-term study may not identify the benefit. (Jacques et al, 1997).

Studies should not be viewed in isolation, because that leads to the "coffee causes cancer" and "coffee reduces cancer risk" absurdity. The effect of a discrepant study such as this is to marginally adjust the current information about risk. Let's say that based on previous studies, as listed below, we thought there was an 80 percent probability that taking vitamins would help to prevent cataracts; after this one we might revise that to 75 percent. This is known as Bayesian probability [after an English minister 300 years ago] and makes a whole lot more sense than the supposedly black-and-white, 95% confidence-interval type of statistics used here. If a gambler isn't a Bayesian he's an idiot; every hand, every throw, alters the odds. So does every study.

The conclusions here are also dodgy because there is no real data on the amounts of the vitamins taken - only a guesstimate from an earlier study of 248 men - and even occasional use was tabulated as use of supplements. For this to make a substantial difference to the health outcome isn't really plausible.

So, in real life?

To prevent age-related diseases of the eye including cataracts, the best current advice is to lower oxidative stress by stopping smoking, reduce excess weight (diabetes again), eat an excellent diet along with a multivitamin supplement and additional supplements of vitamin C (3,000 - 6,000 mg/day in divided doses), vitamin E (400-1,200 IU of natural mixed tocoperols and tocotrienols). This will greatly help prevent oxidation of the tissues of the eye. Artificial forms of vitamin E (dl-alpha-tocopherol) are only 50% as biologically active as the natural form (d-alpha-tocopherol). Taking alpha-tocopherol alone is thought to lower the effective uptake of the other beneficial forms of vitamin E, so it's important to take the natural form of mixed (alpha-, beta-, gamma-, delta-) tocopherols.

(Dr. Damien Downing is a practicing physician specializing in orthomolecular medicine in London, UK, and Dr. Robert G. Smith is a neurophysiologist specializing in eye research at the University of Pennsylvania.)

(I don't have a picture of a Swedish epidemiologist, so here's a Swedish battleship. Technically a Sverige class coastal defense ship, a small battleship of limited speed and range built for defending Sweden's shoreline and harbours.)

References:

1. http://www.dailymail.co.uk/health/article-2283178/How-vitamin-pills-raise-risk-cataracts-hidden-danger-everyday-supplements-revealed.html

2. Selin JZ, Rautiainen S, Lindblad BE, Morgenstern R, Wolk A High-Dose Supplements of Vitamins C and E, Low-Dose Multivitamins, and the Risk of Age-related Cataract: A Population-based Prospective Cohort Study of Men (2013) American Journal of Epidemiology, published online. DOI: 10.1093/aje/kws279

Vitamin C lowers cataract risk:

Head KA. Natural therapies for ocular disorders, part two: cataracts and glaucoma. Altern Med Rev. 2001 Apr;6(2):141-66. [vitamin C alone or with vitamin E reduces risk of cataracts]

Jacques PF, Taylor A, Hankinson SE, Willett WC, Mahnken B, Lee Y, Vaid K, Lahav M. Long-term vitamin C supplement use and prevalence of early age-related lens opacities. Am J Clin Nutr. 1997 Oct;66(4):911-6. [Huge effect, 77% - 83% decrease in lens opacities]

Vitamin E lowers cataract risk:

Rouhiainen P, Rouhiainen H, Salonen JT. Association between low plasma vitamin E concentration and progression of early cortical lens opacities. Am J Epidemiol. 1996 Sep 1;144(5):496-500.

Nourmohammadi I, Modarress M, Khanaki K, Shaabani M. Association of serum alpha-tocopherol, retinol and ascorbic acid with the risk of cataract development. Ann Nutr Metab. 2008;52(4):296-8. doi: 10.1159/000148189.

Seth RK, Kharb S. Protective function of alpha-tocopherol against the process of cataractogenesis in humans. Ann Nutr Metab. 1999;43(5):286-9.

Engin KN. Alpha-tocopherol: looking beyond an antioxidant. Mol Vis. 2009;15:855-60. [ vitamin E likely plays a role in preventing cataracts]

Smoking increases risk:

Mosad SM, Ghanem AA, El-Fallal HM, El-Kannishy AM, El Baiomy AA, Al-Diasty AM, Arafa LF. Lens cadmium, lead, and serum vitamins C, E, and beta carotene in cataractous smoking patients. Curr Eye Res. 2010 Jan;35(1):23-30. doi: 10.3109/02713680903362880.

Hiller R, Sperduto RD, Podgor MJ, Wilson PW, Ferris FL 3rd, Colton T, D'Agostino RB, Roseman MJ, Stockman ME, Milton RC. Cigarette smoking and the risk of development of lens opacities. The Framingham studies. Arch Ophthalmol. 1997 Sep;115(9):1113-8.

Healthy diet prevents cataracts:

Mares JA, Voland R, Adler R, Tinker L, Millen AE, Moeller SM, Blodi B, Gehrs KM, Wallace RB, Chappell RJ, Neuhouser ML, Sarto GE; CAREDS Group. Healthy diets and the subsequent prevalence of nuclear cataract in women. Arch Ophthalmol. 2010 Jun;128(6):738-49. doi: 10.1001/archophthalmol.2010.84.

Williams DL. Oxidation, antioxidants and cataract formation: a literature review. Vet Ophthalmol. 2006 Sep-Oct;9(5):292-8.

2013 Jan-Feb;52(1):62-6. doi: 10.1053/j.jfas.2012.08.003. Epub 2012 Sep 15.

Efficacy and safety of high-dose vitamin C on complex regional pain syndrome in extremity trauma and surgery--systematic review and meta-analysis.

Shibuya N, Humphers JM, Agarwal MR, Jupiter DC.

Source

Texas A&M Health and Science Center, College of Medicine, Temple, TX, USA. shibuya@medicine.tamhsc.edu

Abstract

Complex regional pain syndrome (CRPS) is a devastating condition often seen after foot and ankle injury and surgery. Prevention of this pathology is attractive not only to patients but also to surgeons, because the treatment of this condition can be difficult. We evaluated the effectiveness of vitamin C in preventing occurrence of CRPS in extremity trauma and surgery by systematically reviewing relevant studies. The databases used for this review included: Ovid EMBASE, Ovid MEDLINE, CINAHL, and the Cochrane Database. We searched for comparative studies that evaluated the efficacy of more than 500 mg of daily vitamin C. After screening for inclusion and exclusion criteria, we identified 4 studies that were relevant to our study question. Only 1 of these 4 studies was on foot and ankle surgery; the rest concerned the upper extremities. All 4 studies were in favor of this intervention with minimal heterogeneity (Tau(2) = 0.00). Our quantitative synthesis showed a relative risk of 0.22 (95% confidence interval = 0.12, 0.39) when daily vitamin C of at least 500 mg was initiated immediately after the extremity surgery or injury and continued for 45 to 50 days. A routine, daily administration of vitamin C may be beneficial in foot and ankle surgery or injury to avoid CRPS. Further foot and ankle specific and dose-response studies are warranted.

http://www.ncbi.nlm.nih.gov/pubmed/22985495

Metformin is generally considered to be a drug with few vices, so I was intrigued to read some tweets a while back that mentioned GI upsets in patients. Wikipedia lists these:

"The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting and increased flatulence; metformin is more commonly associated with gastrointestinal side effects than most other antidiabetic drugs. Gastrointestinal upset is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common."

These are side effects one associates with fibre, especially of the FODMAPs type. It occurred to me that if metformin was inhibiting the uptake of dietary carbohydrate this could account for the effect, as sugars would then became more available to gut bacteria, the population of which would tend to regain balance over time (as potato experimenters have recently reported on the resistant starch kick).
The science is conflicting on this, but most papers seem to find some reduction in glucose absorption, e.g. "The results suggest that metformin decreases intestinal glucose absorption in a dose-dependent manner by effects on mucosal and serosal glucose transfer."This raises the possibility that some of Metformin's effects are produced through carbohydrate restriction, and others through increased butyrate production, as well as any localised effects on cells. Both Metformin and butyrate activate AMPK and protein-kinase A.

This is a simple explanation; I ran it past Silvia Price, who unlike me has extensive clinical experience with Metformin, and she turned up a stunning twist on the theory.
Metformin isn't feeding glucose to the microbiotia directly; it is stimulating the intestinal goblet cells to increase and to produce more mucus. Microbiota, specifically Akkermansia Muciniphila, then harvest sugars from the mucus.

An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice

Abstract

Background Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents.

Objective To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition.

Design C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT).

Results Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p 0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT.

Conclusions Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D.

Comment on another "high-fat diet-induced obese mouse" study:

i. Obesity is associated with a decrease in the abundance of Akkermansia muciniphila in gut microbiota.
ii. Akkermansia muciniphila is able to cross-talk with the intestinal epithelium to control gut barrier functions in the pathophysiology of obesity. We show for the first time that obesity is associated with a decrease in the mucus layer thickness recovering epithelial cells. Interestingly, Akkermansia muciniphila is the dominant human bacterium that abundantly colonizes this nutrient-rich environment. We found that living Akkermansia muciniphila was able to control mucus layer production by the host and restore mucus layer thickness in high-fat diet-induced obese mice thereby reducing gut permeability.
iii. Akkermansia muciniphila decreases lipid storage and increases lipid oxidation in high-fat diet obese mice.
iv. Akkermansia muciniphila counteracts inflammation associated to obesity.
v. Akkermansia muciniphila controls high-fat diet-induced obesity and type-2 diabetes.

Goblet cells. Not at all clear what's going on here, chosen for the nice colours.

I wonder if the missing glucose, when and if it does go missing, is being used as the substrate for mucopolysaccharide synthesis by the enhanced goblet cells. I also wonder if it is wise to give Metformin with antibiotics, and whether this increases the risk of Clostridium or Salmonella infection - or indeed, decreases it.

[Goblet] cells that line the gut extrude long chains consisting of exotic and familiar sugars linked together and known by a catch-all term: mucus. This homely product serves two valuable functions. First, by coating the inside intestinal wall, mucus forms a reasonably impervious protective barrier to keep the resident microbes, which serve useful purposes inside the gastrointestinal tract, from getting out of the gut and into the bloodstream, where they could be lethal. But the mucus has a second function as well: It gives our resident microbes a guaranteed source of various sugars, like sialic acid and fucose, that they can snap off and use in a number of ways. They can, for example, break these sugar molecules down and derive energy from them."We believe that bacterial pathogens in the gut cause disease in two steps," he continued. "Others have shown that once these pathogens attain sufficient numbers, they use inflammation-triggering tricks to wipe out our resident friendly microbes ― at no cost to the pathogens themselves, because they've evolved ways to deal with it. But first, they have to surmount a critical hurdle: In the absence of the inflammation they're trying to induce, they have to somehow reach that critical mass. Our work shows how they go about it after a dose of antibiotics. They take advantage of a temporary spike in available sugars liberated from intestinal mucus left behind by slain commensal microbes." (From Scicasts).

Note that pretreatment with Metformin lowered HCV viral load by 0.52 log in insulin-resistant patients in this small study.

On a personal note, I have started an 8-week trial of Sofosbuvir and GS-5816 (Vulcan). It is day 11 and it seems tolerable so far.
A pre-trial blood test on 22nd October was normal except for these counts:
AST 74
ALT 174
and viral load was 600,419 (log 5.78), counts consistent with the tests I've had done this last year.

But the day the trial started, 18th November, before my first dose, things were different:
AST 21
ALT 32
Viral load 27,167 (log 4.43)

The low viral load is easy to explain; I get a consistent 1 log drop (to 14,000-60,000) when I try to eat very low carb (50g/day or lower) and an elevation to 400-600,000 when my carbohydrate intake is over 50g/day. When I ate very high carb (but took antioxidant supps) it was as high as it was on 22nd October. So for me the tipping point seems to be where ketosis begins, and other variations don't have much effect; it's an on/off switch, not a dial (and the name of that switch is PPAR-alpha).
(I do however, according to CAPSCAN elastography, have zero excess fat in my liver, which is an effect of low carb in general, as well as avoiding vegetable seed oils).

The perfect AST and ALT are harder to explain. They have never been so good, not since 1991 when they were first measured. Is it the 30mg/day zinc (as gluconate) I started over a month ago? That would be cool. It's already fixed any lingering fatigue and helped me sleep better.

Grant Schofield, Professor of Public Health at AUT, has done brilliant work bringing LCHF science to the mainstream media in New Zealand. To someone like myself, who enjoys science best when the most cautious and rigorous approach delivers the most revolutionary findings, Prof Schofield's approach to publicity has been exemplary. I missed the interview where he said the LCHF approach would be best for Maori, but caught the response of Maori health provider Toi Tangata:

A public health specialist says Maori should go back to a pre-European diet to stop chronic diseases such as diabetes and cancer - advice disputed by a Maori health organisation.

Auckland University of Technology Professor of Public Health Grant Schofield believes Maori should revert to a diet that debunks a founding pillar of modern nutrition: that a healthy diet is low in fat.

"What Maori ate before Pakeha turned up was most likely a diet that was highish in fat, moderate in protein and relatively low in carbohydrate, and that's true across the whole Pacific region. And you can go and study people who are still eating that way, who are more or less disease free."

His diet plan has been met with a warning from Toi Tangata, a national Maori health provider, which says there's insufficient research to support it and goes on to call the suggestion "faddish and strange".

The health provider's nutritionist, Mason Ngawhika, says Maori could get dangerous mixed messages and think it's okay to eat large quantities of fatty foods without the required balance of fruit and vegetables.

He says the diet plan is too expensive for low-income Maori and such a large diet overhaul would result in too much willpower being required, ending with what nutritionists call the "what-the-hell-effect".

Despite its concerns, Toi Tangata says the diet could have benefits for people who have, or could develop, diabetes.

This is response is not the ringing put-down it might seem at first. The last paragraph makes it obvious that Mason Ngawhika knows enough about LCHF diets for diabetes to accept the evidence for their effectiveness, and diabetic and pre-diabetic are descriptions that include a larger proportion of Maori than of Pakeha. For example, here Maori have many times the rate of diabetes complications compared to non-Maori.
Population rates of renal failure with concurrent diabetes (aged 15+) were over eight-and-a-half times higher in Māori compared with non-Māori (RR 8.78, CI 7.88–9.79). Because the self-reported prevalence of diabetes is similar for Māori and non-Māori, the significantly higher rate of renal failure with concurrent diabetes would suggest that, among people with diabetes, Māori may be up to 8.8 times more likely than non-Māori to go on to develop renal failure (one of the complications of diabetes).

Similarly, population rates of lower limb amputation with concurrent diabetes were over four-and-a-half times higher for Māori compared with non-Māori (RR 4.70, CI 4.01–5.52). Therefore, among people with diabetes, lower limb amputations for Māori can be estimated as being up to 4.7 times more likely than for non-Māori.

Other objections made by Mason Ngawika are also valid; the cost of any new diet is an issue for low-income earners, and adherence to dietary changes - especially those made by people acting for themselves - as well as perceptions of "strangeness" may be significant barriers in the context of Maori family life, where the generous sharing of kai (food) is tikanga (custom).

Research into, and evidence for LCHF is accruing all the time; more importantly, its acceptance is no longer automatically blocked or ignored, the public increasingly expects it to be addressed properly, like the results of any valid science about the important subject of health.

The concern about mixed messages around what are perceived fatty foods is also valid; we don't want to be giving deep-fried food the OK, and some people will always hear what they would like to hear from any message. Then, you just try changing their minds - you'll be accused of changing yours.

So there are significant obstacles against getting the right message across

Here is a presentation which NZ Paleo nutritionist Julianne Taylor made to a Maori organisation last year on the benefits of ancestral diets.

We can run into a problem prescribing LCHF to Maori as ancestral; New Zealand had no native land mammals, so Maori, as Maori, cannot have eaten relatives of pig, sheep, cows, goats or deer. Coconuts, olives, avocadoes and other fatty fruits did not grow here.
Seal are protected and Moa are extinct; so should a modern equivalent of an ancestral Maori diet be based on chicken, fish and shellfish?

Well, no. The most current reliable evidence strongly indicates that initial settlement of New Zealand occurred around 1280CE at the end of the medieval warm period.

The ancestors of New Zealand Maori probably left coastal Asia around 4,000 years ago, well within the Neolithic period. Therfore, in terms of evolutionary adaptation the foods of coastal Asia and the Asian and Melanesian archipelagos are fully ancestral for Maori, and this includes pigs, deer, and buffalo (i.e. land mammals, including ruminant species). Coconut too.

When Europeans arrived in New Zealand, six introduced cultigens (cultivated plants that have no known wild ancestor) were being grown by Māori. They were:

kūmara (sweet potato, Ipomoea batatas)
hue (bottle gourd, Lagenaria siceraria)
aute (paper mulberry, Broussonetia papyrifera)
taro (Colocasia esulenta)
uwhi (yam, Dioscorea species)
tī pore (Pacific cabbage tree, Cordyline fruticosa).

The history book I read a while ago stated that Kumara, the main starch staple of Maori, was brought by later waka (canoes used in oceanic migrations), giving the new arrivals ascendancy over the earlier settlers (Archaic or Moa Hunter), whose main food sources were becoming rare or extinct. I imagine all such claims are up for rebuttal, but it seems to me that only a people desperately short of food would consume bracken roots (aruhe - PDF). Most of the cultigens only grew well in Northland and the Bay of Plenty, yet Maori inhabited the whole length of New Zealand, including some offshore island groups. The use of bracken root, by both early Maori and my own Hibernean ancestors, illustrates to me that the need for starchy or sweet food is innate to most peoples, and that sources of carbohydrate in prehistory were often so poor that their caloric contribution to the diet cannot have been great, yet they were still prepared and eaten at considerable effort and some risk. Eating a high-fat diet from giant Moa would have been an easier proposition than eating a high-carb diet from bracken root. ("The British Royal Horticultural Society recommends against consumption of bracken either by humans or livestock, since it contains carcinogens linked with oesophageal and stomach cancer": probably not "safe starches" then.)

I'm not an expert in Maoritanga or in the foods of South-East Asia, but it seems to me that expanding our concept of Maori ancestral diet in this way will make it a lot easier to construct an affordable ancestral diet for modern urban Maori. I mean, that's something that's already being done, no need for my input there, but this expanded ancestral concept may make it easier to explain what's being done and is working already to uninformed skeptics of the Paleo method.

Starches in the form of kumara, and some sugars from berries and cabbage tree (a slightly nauseating, earthy-tasting, but satisfyingly sweet concoction) were definitely important to Maori, and one would restrict them, not because they are not ancestral, they plainly are, but because carbohydrate restriction is a medical solution for problems that ail Maori. Where these problems do not exist, or have been successfully resolved by carbohydrate restriction, traditional types of starches should not be a problem.
What ancestral Maori couldn't have eaten - grains. Interestingly in The Native Diet TV series on Maori TV, which experimented with Paleo diet and Crossfit training for urban Maori families (Julianne Taylor was a consultant for this enjoyable show), paraora (bread) was the food that participants found the hardest to go without - not alcohol, not sugar. This should give food for thought to dietary reformers of all stripes.

Usually I write these blog posts, even the long ones, in one session. So far this post has occupied three days, and I could spend longer at it, but really it's just a bookmark for some ideas.
Here is a traditional Maori recipe I often make myself, made with a minimum of ingredients, but a satisfying and nutritious meal nonetheless:

Boil-Up.

Take enough meat, bone in (a pork hock is good, beware of bacon hock which is too salty; pork chops work, a bit of lamb or beef would work but I haven't tried these). Cover with water, salt and boil it till tender (i.e. the meat begins to come away easily). Then add kumara (peeled, whole or big chucks), add whole small potatoes if you have kids to feed (you can separate these easily when serving), and half a cabbage in big pieces. Boil till the kumara is done and add chopped watercress. Serve when the potato and watercress is cooked.

(alternately, use this proper recipe!)

This is a South American canid, the Maned Wolf.

File:Maned Wolf 11, Beardsley Zoo, 2009-11-06.jpg

This "dog" is a true omnivore, not unlike homo sapiens. It supplements a diet of meat (frogs, fish, lizards and other small game) with fruit, tubers, and sugarcane. These supply up to 51% of its diet. It does not do well in captivity without vegetable foods, In the wild it is susceptible to infestation by the Giant Kidney Worm (Dioctophyme renale), a potentially lethal roundworm it is exposed to by eating fish. It prefers the fruit of the Wolf Apple(Solanum lycocarpum) or lobeira, a tomato like fruit (also related to the Goji or Wolfberry) which is believed to protect it against this parasite (1).
Cindy Engel writes in Wild Health (a 2002 book which is recommended reading for anyone interested in Ancestral Health):
"Although this fruit is more plentiful in certain seasons, the wolf works hard to eat a certain amount throughout the year... researchers at the Brasilia zoo found that when packs of captive wolves were fed lobeira daily, they survived. If lobeira was withheld, all the wolves died. Postmortem examinations revealed giant kidney worm infestations, and it was suspected that lobeira might be controlling these worms in the surviving wolves".
The Maned Wolf also seems unusually susceptible to cancers in captivity (2)

Whether or not the maned wolf is self-medicating, we can learn a lot by looking at its teeth: File:Manedwolfskull.jpg

Teeth adapted, as the Maned Wolf is, to a diet that can be 51% plant based.

Let us compare that with the dentition of Homo Sapiens, a creature adapted to eating a diet similar to that of the Maned Wolf, with, on average, a broadly similar split between animal and plant foods:

Dentition overview

We can clearly see that the dentition of a species need not be specific for its adapted diet. The Maned Wolf finds animals hard to catch and kill; it is not going to lose its carnivorous dentition because it eats fruit (although too much indulgence in the sugar cane could conceivably have that effect in individuals). The ancestral savannah-dwelling hominid, perhaps a former insectivore and fruitarian, finding itself "tuskless in Eden" in Robert Ardrey's evocative words from African Genesis, survived by developing tools that do the work the Maned Wolf's incisors do. Humans have not needed to trade away teeth that are useful for gripping the ends of the cords used to tie spearheads onto shafts, as well as for crushing seeds and roots. We can chop and stab and saw where the Maned Wolf can only tug and gnaw. The leg joints of quadraped mammalian carnivores are well designed for maximum force in tugging as well as speed in leaping and running.

Man is neither of these things (below), but it's fair to say that for quite a few aeons now he has had more in common with the dog than with the sheep. Especially if that dog is the Maned Wolf.

For comparison, the dentition of a Kangaroo, a marsupial herbivore which has evolved separately from the sheep:

This is the Maned Wolf's closest living relative, the Bush Dog, in flagrante delicto. This tough and gregarious 5-8 Kg canid can hunt the 40 Kg peccary, and a pack has been seen hunting a 250 Kg tapir.
It seems to be a wholly carnivorous creature.

File:Bushdogs.jpg

The legs of the Bush Dog are adapted for strength in tugging at its larger prey, whereas those of the Maned Wolf are more suited for leaping on the small, swift creatures that make up its animal diet.

(1) Conservation of the Maned Wolf: fruitful relationships in a changing environment
Orin Courtenay, Canid News 1994
(2) High Incidence of Ovarian Tumours in Maned Wolves (Chrysocyon Brachyurus) at the National Zoological Park, Munson 1991

Effect of the type of beverage and meat consumed by alcoholics with alcoholic liver disease.

Source

Abstract

Factors associated with the presence of nonalcoholic steatohepatitis in patients with chronic hepatitis C.

Source

Abstract

OBJECTIVES:

METHODS:

RESULTS:

CONCLUSION:

The restorative effect of taurine on experimental nonalcoholic steatohepatitis.

Source

Abstract

Background & Aims

Methods

Results

Conclusions

POLYUNSATURATED FATTY ACID COMPOSITION IN ERYTHROCYTE LIPID MEMBRANES IN NASH: UNEXPECTED HETEROGENEITY IN THE N6-N3 RATIO

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

METHODS:

RESULTS:

CONCLUSIONS:

The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1 CHC.

Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats.

Source

Abstract

Results

Cataracts and Vitamins: The Real Story

Is this research?

Is it reliable?

Is it scientifically plausible?

So, in real life?

References:

Vitamin C lowers cataract risk:

Vitamin E lowers cataract risk:

Smoking increases risk:

Healthy diet prevents cataracts:

Efficacy and safety of high-dose vitamin C on complex regional pain syndrome in extremity trauma and surgery--systematic review and meta-analysis.

Source

Abstract

An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice

(1) Conservation of the Maned Wolf: fruitful relationships in a changing environmentOrin Courtenay, Canid News 1994 (2) High Incidence of Ovarian Tumours in Maned Wolves (Chrysocyon Brachyurus) at the National Zoological Park, Munson 1991

(1) Conservation of the Maned Wolf: fruitful relationships in a changing environment
Orin Courtenay, Canid News 1994
(2) High Incidence of Ovarian Tumours in Maned Wolves (Chrysocyon Brachyurus) at the National Zoological Park, Munson 1991